Molecular Medicine: Department Directory

Laura Bohn

Laura Bohn Ph.D.

Chair And Professor, Department Of Molecular Medicine
Phone: (561) 228-2227
Mailing Address:
120 SCRIPPS WAY
JUPITER FL 33458
Research Summary:

Research in the Bohn laboratory is focused on understanding how G protein-coupled receptors function in an endogenous setting to control physiologically relevant processes. We are most interested in receptors that mediate neurological functions, particularly those of the opioid, serotonin and cannabinoid families. Ultimately, our goal is to refine therapeutics- to enhance the benefits and eliminate the side effects. In this manner, we hope to inspire new approaches in treating pain, addiction and mood disorders.

The Bohn laboratory is most widely known for our work in opioid receptors. Early work while in the laboratory of Marc Caron and in collaboration with Robert Lefkowitz at Duke University indicated that barrestin2 plays a critical role in determining the physiological role of the mu opioid receptor (MOR) in vivo. Our laboratory has shown that barrestin2 plays different roles in regulating the MOR depending upon the physiological function assessed. This is very important as activation of the MOR results in multiple physiological processes ranging from the highly desirable suppression of pain perception to the deadly effects of respiratory failure. By determining which barrestin2-mediated signaling pathways are associated with these different physiological outcomes, we aim to elucidate a means to develop potent opioid analgesics that circumvent the adverse side effects. The bulk of our work to date suggests that if we preserve MOR coupling to G proteins, but eliminate the interactions between the receptor and the scaffolding protein, barrestin2, then we may be able to separate analgesic potency from constipation, respiratory suppression, tolerance and physical dependence.

Our lab is now focused on developing tool compounds that will allow us to test these hypotheses. Our agonists are designed, in collaboration with Dr. Tom Bannister of TSRI, to activate MOR in a manner that preserves or improves G protein signaling while eliminating the recruitment of barrestins. In addition to generating potential therapeutic leads, we are very interested in using these tools to elucidate MOR function in vivo. As we refine the pathways underlying different physiological responses, we will then know the signaling mechanisms to preserve and the ones to avoid.

We are also taking a similar approach with the kappa opioid receptors (KOR). The KOR in the midbrain acts to regulate dopamine and serotonin levels and thereby serves as an attractive target for modulating mood and reward thresholds. KOR ligands that display bias towards or against recruiting barrestins are of interest as barrestin2 has been implicated in facilitating aversive KOR-mediated behaviors. In our work with Dr. Jeff Aubé of Kansas University, we have been developing and evaluating KOR biased agonists to determine which physiologies are preserved or disrupted in mouse models. Since the KOR is involved in diverse physiological functions, compounds generated in this project may serve as interesting candidates for the treatment of depressive disorders and addiction. Moreover, KOR agonism produces antinociception and blocks itch and may also represent potential therapeutic avenues.

Recently, we have begun evaluating ligands for biased agonism among cannabinoid receptor (CB1 and CB2) agonists in collaboration with Dr. Alex Makriyannis at Northeastern University. Given the emerging implications for using cannabinoids as therapeutics for a wide-range of disorders, there are many opportunities for new drug development. This collaboration has also involved working with Dr. Ray Stevens (USC) and Dr. James Liu (Shanghai Tech) to solve the first crystal structures of antagonist and agonist bound CB1 receptors. Additional efforts in the laboratory focus on evaluating how antipsychotic drugs and mood altering neurotransmitters such as serotonin act at serotonin receptors.

Since the receptors described above are involved in modulating mood, motivation, and sensory perception, it stands to reason that our laboratory is most interested in developing means to treat pain, whether due to injury, disease or mental state, in a manner that adequately manages the pain, without causing deabilitating side effects.

Publications:
Grants:
  • Apr 2022 ACTIVE
    Structure and Function of CB2 Receptor
    NORTHEASTERN UNIV · Principal Investigator
  • Apr 2022 ACTIVE
    Synthesis and Evaluation of Functionally Biased Opioid Analgesics
    NATL INST OF HLTH NIDA · Principal Investigator
  • Apr 2022 ACTIVE
    Pharmacological interactions between conventional and biased MOR agonists
    NATL INST OF HLTH NIDA · Principal Investigator
  • Apr 2022 ACTIVE
    Opioid Impacts on T Cell Pathways and Epigenetics to Modulate HIV Integration, Latency and Reservoirs
    UNIV OF CALIFORNIA SAN DIEGO · Principal Investigator
  • Apr 2022 ACTIVE
    Biased Kappa Opioid Agonists as Non-addictive Analgesics
    WAKE FOREST UNIV · Principal Investigator
Education:
  • 1999
    Ph.D. in Biochemistry & Molecular Biology
    Saint Louis University, School of Medicine
  • 1993
    Bachelor's of Arts in Chemistry
    Virginia Polytechnic Institute and State University
  • 1993
    Bachelor's of Science in Biochemistry
    Virginia Polytechnic Institute and State University
Michael Cameron

Michael Cameron Ph.D.

Sr Scientific Director, Associate Professor Of Molecular Medicine, Department Of Molecular Medicine
Phone: (561) 228-2223
Mailing Address:
Room A201
110 SCRIPPS WAY #2A1
JUPITER FL 33458
Research Summary:

The Cameron Laboratory works on a variety of independent and collaborative projects centered on the metabolic fate of new chemical compounds. We explore the role of drug metabolism in chemical induced toxicity and drug-drug interactions. Current projects include evaluation of reactive metabolites and their role in drug induced toxicity, time and mechanism based inhibition of cytochrome P450, and the development of chemical tools to differentiate CYP3A4 and CYP3A5 activity in biological samples. The lab is also involved in several translational projects focused on the development of clinical candidates or molecular probes for the study of biological pathways. The lab offers Drug Metabolism and Pharmacokinetics (DMPK) expertise, collaborating with medicinal chemistry, biology and pharmacology groups. The lab evaluates such factors as chemical and metabolic stability, solubility, oral absorption, rat and mouse pharmacokinetics, tissue distribution, protein binding, P450 inhibition, reactive intermediate formation, and metabolite identification to help refine molecules. Current projects include optimization of neuropeptide Y Y2 receptor antagonists, orexin-1 receptor antagonists, (GABA) B receptor positive allosteric modulators, neurotensin 1 receptor agonists, a5* nicotinic acetylcholine receptors, positive allosteric modulators, kappa opioid receptor antagonists, and functionally biased mu opioid receptor agonists.

Publications:
Grants:
  • Apr 2022 – May 2022
    Covalent Inhibition as a Method to Counteract Botulinum Intoxication
    SCRIPPS RESEARCH INST · Principal Investigator
  • Apr 2022 ACTIVE
    Mitochondrial therapeutics for healthy brain aging
    NATL INST OF HLTH NIA · Co-Investigator
  • Apr 2022 ACTIVE
    Identification of REV-ERB inverse agonists for cancer immunotherapy
    NATL INST OF HLTH NCI · Project Manager
  • Apr 2022 ACTIVE
    Synthesis and Evaluation of Functionally Biased Opioid Analgesics
    NATL INST OF HLTH NIDA · Co-Investigator
  • Apr 2022 ACTIVE
    Synthesis of peripherally active CB1 agonists as analgesics
    UNIV OF HLTH SCIENCES & PHARM ST LOUIS · Principal Investigator
  • Apr 2022 ACTIVE
    Identification of novel anthelmintics through a target-based screen of a parasite ion channel
    MEDICAL COLLEGE OF WISCONSIN · Co-Investigator
Education:
  • 2000
    Ph.D. in Biochemistry
    Utah State University
  • 1994
    Bachelor's of Science in Chemistry
    Gonzaga University
Michalina Janiszewska

Michalina Janiszewska Ph.D.

Assistant Professor
Phone: (561) 228-2788
Mailing Address:
120 SCRIPPS WAY
JUPITER FL 33458
Publications:
Education:
  • 2012
    Ph.D. in Life Sciences
    University of Lausanne
  • 2007
    Master's of Science in Medical Biotechnology
    University of Wroclaw
  • 2005
    Bachelor's of Science in Biotechnology
    University of Wroclaw
Donald G Phinney

Donald G Phinney Ph.D.

Professor
Phone: (561) 228-2214
Mailing Address:
120 SCRIPPS WAY
JUPITER FL 33458

Dr. Phinney received his B.A. in Chemistry and Mathematics from the University of Vermont and a Ph.D. in Biochemistry from Temple University School of Medicine in Philadelphia. He then completed his post-doctoral studies at the Fox Chase Cancer Center where he was awarded an American Cancer Society Fellowship to examine the transcriptional regulation of the JunB oncogene. Dr. Phinney then spent nine years at Tulane University Health Sciences Center where he advanced through the ranks to Professor of Immunology and Microbiology and Associate Director of Research for the Center for Gene Therapy. He joined Scripps Florida in 2009 and is currently a Professor in the Department of Molecular Medicine.

Research Summary:

The Phinney lab combines basic and translational research and drug discovery to deliver highly efficacious cell-based and drug-based therapies for the treatment of skeletal-related pathologies and cancer. Currently the lab is pursuing several different areas of investigation to achieve these goals. One area of focus is directed at enhancing the potency and improving the efficacy of mesenchymal stem cell (MSC)-based therapies, which are widely used in regenerative medicine for the treatment of ischemic and immune-related diseases. These efforts have culminated in the development of a Clinical Indications Prediction (CLIP) Scale that may be used to develop MSC-based therapies tailored to specific disease indications. Ongoing work is directed at validating the CLIP scale and expanding its range of applications. Another area of focus is directed at understanding the molecular mechanism that drive skeletal pathology in response to diet-induced obesity, mechanical unloading (disuse), and chronological aging using mouse models. In these studies, emphasis is on evaluating how these conditions impact the frequency and function of nice resident skeletal stem cells in bone marrow and developing therapeutics to preserve bone integrity. Lastly, the laboratory is also pursuing development of small molecule therapeutics to augment the efficacy and reduce the toxicity of existing chemotherapeutics and immuno-therapies for treating breast cancer.

Publications:
Grants:
  • Apr 2022 ACTIVE
    A Clinical Indications Prediction (CLIP) Scale for Human Mesenchymal Stem Cells
    NATL INST OF HLTH NHLBI · Principal Investigator
Education:
  • 1990
    Ph.D. in Biochemistry
    Temple University, School of Medicine
  • 1984
    Bachelor's of Arts in Chemistry and Mathematics
    The University of Vermont
Huan Bao

Huan Bao Ph.D.

Assistant Professor
Phone: (561) 228-2570
Email: baoh@ufl.edu
Mailing Address:
2A2
130 SCRIPPS WAY
JUPITER FL 33458
Physical Address:
Room A227
110 Scripps Way
Jupiter FL 33458

Lab: https://bao.scripps.ufl.edu or https://sites.google.com/view/baolab

Research Summary:

We seek to develop biochemical and genetic tools that allow us to understand and manipulate membrane biology. Specifically, we attempt to expand the function and geometry of lipid nanoparticles (LNP) for mechanistic dissections of membrane proteins. We are using these new lipid nanoparticles to push the frontier in the following four directions: 1) mechanistic understandings of exosome secretion involved in cancer and neurological disorders; 2) structural elucidation of membrane protein complexes unattainable in previous studies; 3) vaccine development and drug discovery to control viral infection; 4) cell reprogramming that would enable continuously evolution of protein binders against cell-surface antigens. We characterize the performance of our tools biochemically, structurally, and in cells and animal models.

Research Interests:
  • lipid nanoparticle
  • membrane protein
  • single molecule biophysics
Grants:
  • Apr 2022 ACTIVE
    Developing next-generation nanodiscs for the study and modulation of membrane proteins
    NATL INST OF HLTH NIGMS · Principal Investigator
Education:
  • 2014
    Ph.D. in Biochemistry
    University of British Columbia
  • 2008
    Master's of Science in Biochemistry
    Chinese Academy of Sciences
  • 2005
    Bachelor's of Science in General Biology
    Wuhan University
Thomas Bannister

Thomas Bannister Ph.D.

Research Professor (Sr. Scientific Director), Department Of Molecular Medicine
Phone: (561) 228-2206
Mailing Address:
130 Scripps Way # A229
UF Scripps Biomedical Research
Jupiter FL 33458
Physical Address:
110 Scripps Way #A229
UF Scripps Biomedical Research
Jupiter FL 33458
Research Summary:

Organic/Medicinal Chemistry and Drug Discovery

The discovery of possible drug candidates is a highly collaborative endeavor, with medicinal chemistry as a core, problem-solving component. My major research efforts are joint projects with world experts in cancer biology and neuroscience, wherein my group provides the organic and medicinal chemistry expertise and drug design insights. In general, we strive to find novel ways to target poorly-treated, common, and devastating disorders that increasingly burden world health care systems.

Neuroscience studies include:

— Biased mu opioid agonists, aiming for a holy grail of sorts: to separate the robust pain relief –provided by opiates from their many unwanted side effects. This collaboration with Laura Bohn’s group has led to findings published in 2017 in Cell, with follow-up chemistry disclosure in the Journal of Medicinal Chemistry in late 2018 (featured on the cover). — NOP agonists, for post-traumatic stress disorder (PTSD) and alcohol addiction relapse therapy. — NAD-elevating neuroprotectants, for Alzheimer’s and Parkinson’s Diseases, and for ALS.

Cancer projects include:

— KLF5 inhibitors for colorectal cancer therapy. — TBK1 and IKKi dual kinase inhibitors, for hormone-refractory prostate cancer. — Inhibitors of kinases CK1delta, ASK1, and ULK1, for various cancers. — Modulators of the HIPPO-YAP pathway, for various cancers. — Other exploratory efforts include:

High-throughput screening-based “chemical probe development”, seeking first-in-class small molecules for investigating the therapeutic potential of new target proteins. Probe development efforts encompass multiple therapeutic areas, including treatments for cancers, glaucoma, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), addiction, infectious diseases, and mood disorders. One chemical probe effort targets the orphan GPCR GPR151, a target that may be relevant for the development of treatments for addiction, depression, and schizophrenia.The discovery of possible drug candidates is a highly collaborative endeavor, with medicinal chemistry as a core, problem-solving component. Our major efforts are thus joint projects with world experts in cancer biology and neuroscience, wherein our group provides the organic and medicinal chemistry expertise.

Our cancer projects target unique metabolic phenotypes of tumor cells, identifying defining molecular characteristics to be exploited for the development of targeted therapies. Most tumor types have a shared reliance upon active transport of nutrients and building blocks to drive rapid cancer cell growth and to sustain survival. They also largely rely upon glycolysis for ATP production (the Warburg effect). As examples, we have created molecules to keep tumor cells from exporting lactate, the end product of glycolysis. We have also designed compounds to block amino acid transporters that are up-regulated by many tumors. We have a program targeting expression of a transcription factor that drives colon cancer progression. We also have a number of kinase inhibitor programs aimed the discovery of treatments for brain cancers, triple-negative breast cancer, hormone-resistant prostate cancer, and perhaps other forms as well. This are collaborative efforts with top TSRI cancer biologists including Derek Duckett, Joseph Kissil, Jun-li Luo, and also including John Cleveland from the Moffitt Cancer Center.

Many of our anticancer programs have a computational chemistry-directed focus, relying on molecular modeling based upon published coordinates, virtual screening, scoring, and validation of predicted hits through chemical synthesis. We use the Schrodinger suite of modeling software in these studies. For future work we may have a need to hire postdoctoral scientists with both computational and synthesis experience. Please contact me for further information.

In our neuroscience studies we are developing GPCR agonists that have targeted effects in the brain. We are exploring GPCR signaling bias in mu opioid receptor activation, aiming for a holy grail of sorts: to separate the robust pain relief provided by opiates from their many unwanted side effects. This collaboration with Laura Bohn’s group has led to pain relievers that seem to be devoid of many of the side effects of morphine and related opiates, such as respiratory suppression, heart rate effects, and GI effects (constipation). In a separate study we identified tool compound with promise in an animal model of post-traumatic stress disorder (PTSD).

Other exploratory efforts use medicinal chemistry in concert with high-throughput screening or following HTS campaigns, where we seek to discover and optimize “chemical probes”, or first-in-class small molecules that should prove useful for investigating the therapeutic potential of new target proteins. Such probe development efforts encompass multiple therapeutic areas, including treatments for ALS, Parkinson’s Disease, addiction, infectious diseases, cancers, glaucoma, and mood disorders.

One such chemical probe effort, a collaboration with Patsy McDonald, targets the orphan GPCR GPR151, a target that may be relevant for the development of treatments for addiction, depression, and schizophrenia. In a collaboration with Sathya Puthanveettil we are investigating the potential of facilitating the function of kinesin motor proteins as a novel approach to therapies for Alzheimer’s disease (AD) and frontal temporal dementia (FTD), which are poorly-treated, common, and devastating disorders that increasingly burden world health care systems. In a collaboration with Corinne Lasmezas, we are developing compounds that rescue neurons from toxicity of protein aggregates, relevant for developing new therapies for ALS and Parkinson’s Disease.

As you can tell, collaborative drug discovery research is order of the day in my lab!

Members of my group benefit from interactions not only with other chemists but with top biologists and pharmacologists, as they partake in project team meetings as well as in our weekly chemistry group meetings. My research is funded currently by 8 NIH grants on which I am a co-principal investigator and 8 others NIH grants where I am a named investigator or co-investigator.

On occasion I have openings for outstanding postdoctoral fellows in my labs. As mentioned above, an especially good fit would be a postdoc with lab synthesis experience and with prior expertise in using the Schrodinger suite of molecular modeling software, to aid our virtual screening-based efforts. Our postdoctoral scientists collaborate with a team of biological co-investigators, applying knowledge and experience in modern organic, heterocyclic, and/or medicinal chemistry toward an ongoing drug discovery effort. Excellent communication skills, good synthetic organic chemistry laboratory skills, ability to work in the US, and familiarity with modern synthetic techniques and instrumentation are required in this role. Contact me for further details.

Publications:
Grants:
  • Apr 2022 ACTIVE
    Therapeutic Targeting of Casein Kinase-1-delta in Primary Metastatic Breast Cancer
    H LEE MOFFITT CANCER CTR · Principal Investigator
  • Apr 2022 ACTIVE
    Synthesis and Evaluation of Functionally Biased Opioid Analgesics
    NATL INST OF HLTH NIDA · Principal Investigator
  • Apr 2022 ACTIVE
    Development of New Casein Kinase 1 Inhibitor for the Treatment of Brain Cancers
    H LEE MOFFITT CANCER CTR · Principal Investigator
  • Apr 2022 ACTIVE
    Identification of novel anthelmintics through a target-based screen of a parasite ion channel
    MEDICAL COLLEGE OF WISCONSIN · Co-Investigator
Education:
  • 1991
    Ph.D. in Organic Chemistry
    Indiana University
  • 1987
    Master's of Philosophy
    Yale University
  • 1986
    Master of Science
    Yale University
  • 1984
    A.B. in Chemistry
    Wabash College
Theodore Kamenecka

Theodore Kamenecka Ph.D.

Sr. Scientific Director, Department Of Molecular Medicine
Phone: (561) 228-2207
Mailing Address:
2A1
130 SCRIPPS WAY
JUPITER FL 33458
Physical Address:
Room A230
110 Scripps Way
Jupiter FL 33458
Research Summary:

Medicinal Chemistry and Drug Discovery

The research interest in my group is in the design, synthesis and evaluation of novel compounds of biological and therapeutic interest. Currently, we are involved in the design and synthesis of novel small molecule modulators of nuclear receptors, GPCR’s, ion channels, kinases and mitochondria for the therapeutic treatment of addiction, diabetes and obesity, multiple sclerosis, cognitive health and aging. Working closely with other departments such as molecular biology, pharmacology, and drug metabolism, we optimize lead compounds for potency, ADME (absorption, distribution, metabolism, and excretion), safety pharmacology, and toxicology in order to generate compounds suitable for preclinical development.

Publications:
Grants:
  • Apr 2022 – May 2022
    Identification of Chemical Probes for the Orphan Nuclear Receptor NR2F6
    NATL INST OF HLTH NCI · Co-Investigator
  • Apr 2022 ACTIVE
    ALDH1a1 Inhibition As A Therapeutic Target In Visceral Adiposity and Type 2 Diabetes
    BRIGHAM AND WOMENS HOSPITAL · Co-Project Director/Principal Investigator
  • Apr 2022 ACTIVE
    Mitochondrial therapeutics for healthy brain aging
    NATL INST OF HLTH NIA · Co-Investigator
  • Apr 2022 ACTIVE
    Parallel Multimodal High-throughput screening to identify activators of the orexin receptors
    NATL INST OF HLTH NIMH · Principal Investigator
  • Apr 2022 ACTIVE
    Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma
    NATL INST OF HLTH NINDS · Principal Investigator
  • Apr 2022 ACTIVE
    Identification of REV-ERB inverse agonists for cancer immunotherapy
    NATL INST OF HLTH NCI · Co-Investigator
  • Apr 2022 ACTIVE
    Development of novel therapeutics for opioid dependence
    ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · Principal Investigator
  • Apr 2022 ACTIVE
    Mechanistic studies of corepressor-mediated PPAR? transcriptional repression
    NATL INST OF HLTH NIDDK · Co-Investigator
  • Apr 2022 ACTIVE
    Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma
    NATL INST OF HLTH NINDS · Co-Investigator
  • Apr 2022 ACTIVE
    Targeting Cellular Senescence to Extend Healthspan
    MAYO CLINIC · Principal Investigator
  • Apr 2022 ACTIVE
    Small molecules targeting hepatic glucose production and insulin resistance
    DANA FARBER CANCER INST · Co-Investigator
  • Apr 2022 ACTIVE
    Targeting Go and Grow in Glioblastoma
    MAYO CLINIC · Project Manager
  • Apr 2022 ACTIVE
    Molecular basis of activation of the orphan nuclear receptor Nurr1
    NATL INST OF HLTH NIA · Co-Investigator
Education:
  • 1996-1998
    Post-doctorate
    Memorial Sloan Kettering Cancer Center
  • 1990-1996
    Ph.D. in Chemistry
    University of California, Irvine
  • 1986-1990
    Bachelor of Science in Chemistry
    University of Rochester
Patrick Griffin

Patrick Griffin Ph.D.

Scientific Director And Professor
Phone: (561) 228-2200
Mailing Address:
120 SCRIPPS WAY
JUPITER FL 33458

My scientific career has focused on the study of protein structure and approaches to modulating protein function via synthetic small molecules with a focus on nuclear receptors. I have a broad background in drug discovery and development that spans the last 25+ years. I received a Ph.D. in Chemistry from the University of Virginia under the direction of Professor Donald F. Hunt where I was involved in methodology development in the field of Biological Mass Spectrometry. After graduating from UVa, I was a Postdoctoral Fellow for Professor Leroy Hood at Caltech where I was involved in the application of mass spectrometry to systems biology.

Prior to Scripps, I was Chief Science Officer of ExSAR Corporation, NJ, a biotech company focused the use of HDX mass spectrometry (HDX-MS) to aid in the development of chemical chaperones for protein misfolding disorders. Prior to ExSAR, I was Senior Director, Chemistry, at Merck Research Laboratories where he spent over 11 years applying biological mass spectrometry and proteomics to a wide range of therapeutic areas including metabolic disorders, cardiovascular disease, and infectious diseases. At Merck, I headed the discovery DMPK operation within the Chemistry Department and the Molecular Profiling Proteomics group. My team made significant contributions to over 35 safety assessment programs. Most significant were my team’s contributions towards the discovery and development of MK-0431, a DPP4 inhibitor now in clinical use (Januvia), and towards clinical development of DMP-777, an elastase inhibitor for treatment of cystic fibrosis that progressed to phase IIb trials.

In 2004, I joined The Scripps Research Institute (TSRI) Scripps Florida as Professor and in 2007 was named Professor and founding Chair of the Department of Molecular Therapeutics. As PI, Co-PI, and co-investigator on several NIH-funded grants, my research continues to focus on protein structure and function, particularly on mutational- and ligand-mediated alterations in protein structural plasticity, as well as quantitative SAR to facilitate lead optimization of molecules targeting therapeutic proteins. Using mutagenesis, HDX-MS, crystallography, proteomics and genomics my research is focused on structure-function of nuclear receptors, enzymes, and G protein coupled receptors (GPCRs). My research program has a major focus on understanding nuclear receptor (NR) signaling using structural, chemical and biological approaches. We have made significant contributions to understanding the mechanism of ligand activation of NRs such as PPARs, RORs, REV-ERBs, LRH1, VDR, ER, GR, and PR. We have also made significant contributions dissecting domain-domain interactions in control of positive and negative allostery. Our chemical biology program is focused on the RORs, PPARs, VDR and LRH1. In each of these programs we are developing functionally selective and promoter-specific modulators targeting disease such as cancer, autoimmune, obesity, and diabetes. My lab is well known for the development and application of biophysical methods including our HDX and XL-MS platform for the analysis of protein plasticity with a focus on NRs, enzymes, and GPCRs.

For the first half of my career I was in industry where there was less of an emphasis on publications. However, over the last 16 years as an academic I have published >240 peer-reviewed manuscripts. According to Google Scholar I have an h-index of 83 (58 since 2016) and an i10-index of 223. Below is a URL for My Bibliography of Patrick R. Griffin; some papers are under Griffin P.

Research Summary:

As a graduate student at the University of Virginia, I worked in Don Hunt’s lab alongside John Yates and together we performed ground-breaking studies in the use of mass spectrometry to determine the primary structure of proteins. I am first author on a paper describing the complete sequence of a protein using tandem mass spectrometry. Prior, only a few small proteins for which their amino sequence was known had been sequenced by tandem mass spectrometry. This work helped validate that it was possible to sequence proteins using tandem mass spectrometry. I am first author on one of the first papers describing the using low nano-LC coupled with ESI. I contributed to many other publications demonstrating the use of mass spectrometry for structural analysis of proteins.

While at Merck Research Laboratories, my lab made significant contributions to a wide range of projects including key contributions to the development of the DPP4 program which led to the approval and marketing of Januiva. The range of contributions to drug discovery and development are exemplified in manuscripts listed below. My efforts in drug discovery have continued in the academic setting.

In 2002 I became interested in the application of hydrogen/deuterium exchange mass spectrometry. My lab focused on the development of a fully automated system, advanced software to facilitate robust high precision analysis, and applications of HDX in protein-ligand interactions with an emphasis on nuclear receptors, enzymes, and GPCRs. The publications listed below include an extensive list of key contributions to the HDX field.

In addition to the advancement of structural proteomics, my research has focused on chemical biology approaches to better understand nuclear receptor signaling. Our group described the first synthetic ligand for the orphan nuclear receptor NR1F subfamily (ROR)s and subsequently showed the utility of advanced compounds as anti-inflammatory and anti-obesity agents as well as RORG agonists for enhancing protective immunity in the context of cancer therapy. Our lab has also contributed to a fundamentally new understanding of the mechanism by which the nuclear receptor PPARG impacts insulin sensitivity.

Highlights on grant funding related to drug development programs

• I was consortium PI of the “The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps,” I had both a leadership role and a scientific role on this large multi-center 6-year U54 MLPCN Roadmap initiative.

• I was consortium PI of a RC4 program in collaboration with Bruce Spiegelman at the Dana Faber, I was involved in the discovery and development of novel molecules for the treatment of obesity and diabetes. Work from our labs in this area led us to co-found Ember, a private biotech funded by Third Rock Ventures.

• I was Co-PI on a NIDA funded U19 NCDDDG focused on the discovery and development of novel positive allosteric modulators of GABAB receptor for treatment of nicotine addiction.

• I served on the Scripps-Pfizer collaboration Steering Committee for its 5 year term coordinating collaborative drug discovery programs.

• I am PI of a 13-year long collaboration between my lab and Eli Lilly. • I am PI on a collaborative grant with the private Biotech Synkine Therapeutics.

• I am Co-PI on a NIH Blueprint UH3 titled, “Developing nonmuscle myosin II inhibitors for substance use relapse.” Co-founder of Myosin Therapeutics. The Myosin Therapeutics’ clinical candidate emerged from the NIH Blueprint program.

Publications:
Grants:
  • May 2022 ACTIVE
    Structural dynamics of progesterone receptor-coactivator complexes
    NATL INST OF HLTH NCI · Principal Investigator
  • Apr 2022 ACTIVE
    ALDH1a1 Inhibition As A Therapeutic Target In Visceral Adiposity and Type 2 Diabetes
    BRIGHAM AND WOMENS HOSPITAL · Principal Investigator
  • Apr 2022 ACTIVE
    HIV Interactions in Viral Evolution
    SEATTLE CHILDRENS HOSPITAL · Principal Investigator
  • Apr 2022 ACTIVE
    Developing chemoproteomic approaches to decipher the regulatory network of LRH-1,a nuclear receptor implicated in hepatic metabolism
    NATL INST OF HLTH NIDDK · Principal Investigator
  • Apr 2022 ACTIVE
    Mechanistic analysis of therapeutic targets using hydrogen/deuterium exchange mass spectrometry (HDX MS)
    ELI LILLY AND CO · Principal Investigator
  • Apr 2022 ACTIVE
    Mechanistic studies of corepressor-mediated PPAR? transcriptional repression
    NATL INST OF HLTH NIDDK · Co-Investigator
  • Apr 2022 ACTIVE
    Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma
    NATL INST OF HLTH NINDS · Co-Investigator
  • Apr 2022 ACTIVE
    Small molecules targeting hepatic glucose production and insulin resistance
    DANA FARBER CANCER INST · Principal Investigator
  • Apr 2022 ACTIVE
    Structural Biology of Connexin Membrane Channels
    UNIV OF VIRGINIA · Principal Investigator
  • Apr 2022 ACTIVE
    Chemistry and Biology of ADP-Ribosylation-Dependent Signaling
    UNIV OF SOUTHERN CALIFORNIA · Principal Investigator
  • Apr 2022 ACTIVE
    Ultra-potent HIV capsid inhibitors
    UNIV OF COLORADO DENVER & ANSCHUTZ MED · Principal Investigator
  • Apr 2022 ACTIVE
    Molecular basis of activation of the orphan nuclear receptor Nurr1
    NATL INST OF HLTH NIA · Co-Investigator
Education:
  • 1989
    Ph.D. in Chemistry
    University of Virginia
  • 1985
    Bachelor's of Science in Chemistry
    Syracuse University
Scott Hansen

Scott Hansen Ph.D.

Associate Professor Of Department Of Molecular Medicine
Phone: (561) 228-2415
Mailing Address:
120 SCRIPPS WAY
JUPITER FL 33458
Research Summary:

Our laboratory studies the role of cholesterol in setting thresholds of anesthesia, mechanosensation, amyloid formation, and viral entry. In each area of research, we study how cholesterol controls the threshold that regulates biological function and the severity of disease. By understanding the thresholds, we aim to treat diseases caused by altered cholesterol levels and signaling lipids.

Anesthesia: For hundred years scientist believed that membrane lipids were involved in the anesthesia (reversible loss of consciousness). At the heart of the question was the following, How can disrupting a lipid membrane activate or inhibit and ion channel? We have shown that anesthetics disrupt compartmentalization of signaling molecules in cholesterol dependent lipid compartments. The anesthetics counteract cholesterol causing the proteins to escape and activate an ion channel. This established at least one clear molecular mechanism for the membrane as a target of inhaled anesthetics. We are studying this mechanism for additional ion channels that mediate anesthesia in people.

Pain threshold (mechanosensation): We have shown mechanical force disrupts cholesterol dependent compartmentalization of proteins, similar to anesthetics. In addition to defining a novel mechanosensation pathway, we are developing potential therapeutic compounds that will activate an analgesic channel downstream of mu opioid receptor. We aim to develop therapeutics that will have similar pain reducing benefits as opioids, but without the addiction.

Viral entry: We have recently proposed a model for cholesterol dependent SARS-COV-2 viral infectivity, based on our understanding of cholesterol mediated membrane protein translocation. As cholesterol increases the ability of the virus to enter the cell increases. Increased viral entry increases inflammation, which in turn increases cholesterol and more viral entry. We are currently studying cholesterol loading in lung tissues in aged animals.

Publications:
Grants:
  • Apr 2022 ACTIVE
    The role of lipid raft disruption in the activation of TREK-1 channels by anesthetics
    NATL INST OF HLTH NINDS · Principal Investigator
Education:
  • 2006
    Ph.D.
    University of California, San Diego
  • 1999
    Bachelor's of Science in Chemistry
    Utah State University
Claudio A Joazeiro

Claudio A Joazeiro Ph.D.

Professor
Phone: (561) 228-3211
Mailing Address:
Scripps Way
Jupiter FL 33458

website: www.joazeirolab.com

Research Summary:

See lab website: www.joazeirolab.com

Role of the ubiquitin-proteasome system in cellular regulation and disease

E3 ubiquitin ligases are the components that confer specificity to the ubiquitin system. Consistent with their critical role in cellular regulation, mutations affecting E3s can cause human disease—as illustrated by the cases of BRCA1 in breast cancer and of Parkin in Parkinsonism. Our laboratory is engaged in three main areas of research related to E3s:

1] We are interested in elucidating E3s’ function and mechanisms. For this purpose, we utilize cell and molecular biology approaches with mammalian cells, mice and yeast; our expertise is complemented by close collaborations on structural biology, bioinformatics, mass spectrometry, next-generation sequencing, and fly models;

2]We utilize the information we learn from the above studies to develop assays that are amenable to high-throughput screening, which are then used to identify small molecule inhibitors of E3 ligases. Such compounds can then be both turned into tools to interrogate biology, and developed as pharmaceutical drug candidates;

3] We collaborate with clinicians to translate our basic research findings into therapeutically-relevant discoveries.

Research Interests:
  • Microbiology
  • Molecular therapy
  • Neurodegenerative diseases
  • Protein biochemistry
  • RNA binding proteins
  • Rare neuromuscular disorders
  • Small molecule drug discovery
Publications:
Grants:
  • Jul 2022 ACTIVE
    POLYALANINE TAILS: A NOVEL TYPE OF PROTEIN MODIFICATION IMPLICATED IN NEURODEGENERATION
    THE JACKSON LABORATORY · Principal Investigator
Education:
  • 1996
    Ph.D.
    University of California, San Diego
  • 1990
    Master's of Science
    University of Sao Paulo
Courtney Miller

Courtney Miller Ph.D.

Director Of Academic Affairs And Professor
Phone: (561) 228-2958
Mailing Address:
120 SCRIPPS WAY
JUPITER FL 33458
Research Summary:

The Miller Lab is working to develop new medications for the treatment of disorders marked by persistent, unwanted memories – specifically substance use disorder (SUD; addiction) and posttraumatic stress disorder (PTSD). Mechanistically, our efforts are large focused on epigenetic and synaptic structural players.

DEVELOPMENT OF THERAPEUTICS TO PREVENT ADDICTION RELAPSE

Dr. Miller has long been interested in ways to selectively disrupt drug-associated memories (Reconsolidation; Miller and Marshall, Neuron, 2005) and the mechanisms that contribute to the persistence of memory (DNA methylation; Miller et al, Nature Neuroscience, 2010). In bringing these two areas together, the Miller Lab made the surprising discovery that memories associated with the commonly abused stimulant, methamphetamine, employ a unique, actin-based storage mechanism in the brain’s emotional memory center, the amygdala, that allows for their selective disruption (Young et al, Biological Psychiatry, 2014). This was followed by identification of nonmuscle myosin II (NMII) as a viable therapeutic target (Young et al, Molecular Psychiatry, 2015) and we are now in the middle of a drug development program supported by the NIH’s Blueprint Neurotherapeutics Network to develop a clinically safe NMII inhibitor. The goal is to enter a Phase 1a safety trial in 2020.

REGULATION OF TRAUMATIC MEMORY RELATED TO PTSD

We recently developed an animal model with PTSD-like features, including differential susceptibility, which has been replicated by other groups. The stress susceptible subgroup displays persistent, stress-enhanced fear memory, hyperarousal, amygdala hyperactivation and differential expression of genes with known polymorphisms in human PTSD genomic studies (Sillivan et al, Biological Psychiatry, 2017). Importantly, the stress susceptible population can be identified by training behavior, removing the need for additional phenotyping that introduces a molecular confound. Because the model was developed in an inbred mouse line (c57’s), it’s an excellent opportunity to investigate epigenetic mechanisms. To date we have largely focused on noncoding RNAs, including miRNAs. Small RNA-sequencing integrated with quantitative proteomics revealed a panel of miRNAs persistently upregulated in the amygdala of stress susceptible mice. We recently completed a study demonstrating a functional role for one of these miRNAs, which is also expressed in the human amygdala. Working with our collaborators, we also discovered the miRNA’s passenger strand is elevated in serum of a Dutch military cohort diagnosed with PTSD six months after a combat deployment to Afghanistan, indicating this miRNA may be a therapeutic target and biomarker for PTSD. Efforts are now shifting to in vivo calcium imaging and manipulation of the activity-dependent neuronal ensembles regulating differential susceptibility to stress.

Publications:
Grants:
  • Apr 2022 ACTIVE
    Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma
    NATL INST OF HLTH NINDS · Principal Investigator
  • Apr 2022 ACTIVE
    Circuit-level substrates of ASD-related cognitive and behavioral impairments
    NATL INST OF HLTH NIMH · Principal Investigator
  • Apr 2022 ACTIVE
    Preventing alcohol seeking with a nonmuscle myosin II inhibitor under clinical development
    NATL INST OF HLTH NIAAA · Principal Investigator
  • Apr 2022 ACTIVE
    Assessing the role of circRNAs in memory consolidation
    NATL INST OF HLTH NIMH · Co-Investigator
  • Apr 2022 ACTIVE
    Developing nonmuscle myosin II inhibitors for the treatment of glioblastoma
    NATL INST OF HLTH NINDS · Principal Investigator
  • Apr 2022 ACTIVE
    Integrated Platform for Discovery and Validation of Probes that Restore Protein Expression in Single-Gene Causes of Autism and Related Disorders
    NATL INST OF HLTH NIMH · Principal Investigator
  • Apr 2022 ACTIVE
    Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory
    NATL INST OF HLTH NIDA · Principal Investigator
  • Apr 2022 ACTIVE
    Targeting Go and Grow in Glioblastoma
    MAYO CLINIC · Principal Investigator
Education:
  • 2005
    Ph.D. in Neurobiology
    University of California, Irvine
  • 1999
    Bachelor's of Science in Biopsychology
    University of California, Santa Barbara
Louis Scampavia

Louis Scampavia Ph.D.

Senior Scientific Director: Department Of Molecular Medicine
Phone: (561) 228-2101
Mailing Address:
130 SCRIPPS WAY
JUPITER FL 33458
Physical Address:
110 SCRIPPS WAY # 1A1
JUPITER FL 33458
Research Summary:

Progress in drug discovery is often coupled to parallel advancements in instrument technology. In our department, High Throughput Screening (HTS) robotics is employed to accelerate the drug discovery process thorough full automation of large scale screening experiments. HTS technology can be used to execute and analyze hundreds of thousand of experiments against large compound libraries to identify a few select compounds of therapeutic value. These “therapeutic leads” provide important insight and basis for the medicinal development of novel drugs for clinical application.

Research efforts are currently focused on:

— Working with collaborators to develop biological assays for HTS compatibility.

— Performing exploratory HTS campaigns for drug lead discovery.

— Technology development and instrumentation for the advancement of HTS robotics.

Collaborative efforts are coordinated with a large community of scientists and include TSRI and UF faculty, Florida researchers, and academia often funded through the National Institutes of Health, Department of Defense and private foundations.

Publications:
Grants:
  • Jun 2022 ACTIVE
    Takeda TCAL GPCR HTS
    TAKEDA PHARM NORTH AMERICA · Co-Investigator
  • Apr 2022 – May 2022
    Identification of Chemical Probes for the Orphan Nuclear Receptor NR2F6
    NATL INST OF HLTH NCI · Principal Investigator
  • Apr 2022 ACTIVE
    Development of neutral ceramidase inhibitor tool compounds
    THE RES FOU FOR THE SUNY STONY BROOK UNI · Principal Investigator
  • Apr 2022 ACTIVE
    An Innovative Approach to Identify Correctors of Metabolic Complications in HIV
    SCRIPPS RESEARCH INST · Co-Investigator
  • Apr 2022 ACTIVE
    Tandem Multi-modal Plate Readers for a High Throughput Screening platform
    NATL INST OF HLTH OD · Principal Investigator
  • Apr 2022 ACTIVE
    Parallel Multimodal High-throughput screening to identify activators of the orexin receptors
    NATL INST OF HLTH NIMH · Principal Investigator
  • Apr 2022 ACTIVE
    Drug Discovery for First-In-Class Myosin 10 Inhibitors as a Novel Target for Glioblastoma
    NATL INST OF HLTH NINDS · Principal Investigator
  • Apr 2022 ACTIVE
    Identification of small molecules for neurological complications of HIV and substance abuse comorbidity
    SCRIPPS RESEARCH INST · Co-Investigator
  • Apr 2022 ACTIVE
    Identification of REV-ERB inverse agonists for cancer immunotherapy
    NATL INST OF HLTH NCI · Principal Investigator
  • Apr 2022 ACTIVE
    High-Throughput Screen for the Oncoprotein MYC
    SCRIPPS RESEARCH INST · Co-Investigator
  • Apr 2022 ACTIVE
    Integrated Platform for Discovery and Validation of Probes that Restore Protein Expression in Single-Gene Causes of Autism and Related Disorders
    NATL INST OF HLTH NIMH · Principal Investigator
  • Apr 2022 ACTIVE
    Identification of novel anthelmintics through a target-based screen of a parasite ion channel
    MEDICAL COLLEGE OF WISCONSIN · Principal Investigator
Education:
  • 1996
    Doctor of Philosophy in Chemistry
    University of Washington, Seattle
  • 1991
    Bachelor's of Science in Chemistry
    University of Washington, Seattle
  • 1979
    Bachelor's of Science in Genetics
    University of California, Berkeley
Timothy P Spicer

Timothy P Spicer Ph.D.

Senior Scientific Director, Department Of Molecular Medicine
Phone: (561) 228-2150
Mailing Address:
110 SCRIPPS WAY RM A113 # 1A1
JUPITER FL 33458
Physical Address:
110 SCRIPPS WAY RM A113 # 1A1
JUPITER FL 33458
Research Summary:

The focus of our research involves enabling technologies for High Throughput Screening (HTS) of any target of unmet therapeutic need. Our facility supports scientist and faculty locally as well as those in the US and throughout the world. We do this by implementing their biological applications into high density plates for HTS. The breadth of biology we deal with is virtually unlimited due to the diversity of skill sets of the scientist and engineers within our group as well as the expanded capability of the readers associated to our system. We operate a fully automated 1536 well compatible platform and perform HTS on large compound libraries such as the Scripps Drug Discovery Library (645K) or small focused collections (FDA approved drugs). We have expertise in microfluidics, low nanoliter volume liquid handling, ultra-sensitive plate reader technologies and informatics set-up to handle large volume data sets. Key components are high-content readers, imaging detectors such as the ViewLux and FLIPR Tetra, as well as pintool and acoustic transfer devices. Through collaborative efforts we have successfully translated multiple small molecules into the clinics. We are open to any pharmacology desired (agonist, PAMs, NAMs, inverse agonist, etc.) vs. kinases, GPCR, NHRs, proteases, phenotypic assays, etc. which can be applied to any therapeutic area; i.e. CNS, infectious diseases, cardiovascular, oncology, metabolic diseases. In addition, we are currently funded (R33CA206949) to develop 3D spheroid based uHTS assays for the purpose of testing molecules in a more phenotypically relevant format to cancer biology.

Publications:
Education:
  • 2019
    Ph.D. in Medicine
    University of Queensland
  • 1996
    Master's of Microbiology
    State University of New York Health Science Center
  • 1990
    Bachelor's of Science in Biology
    State University of New York at Albany