Related Disease: Neurological and Psychiatric Disorders
Dr. Piña-Crespo earned a PhD in Pharmacology from University College London (UCL), England under the supervision of Profs. Alasdair Gibb & David Colquhoun FRS. He completed postdoctoral training as a Pew Fellow/Research Associate with Prof. Steve Heinemann in the Molecular Neurobiology Laboratory at The Salk Institute, La Jolla, California. Dr. Piña-Crespo has held faculty positions as Instructor and Assistant Professor at Universidad Centroccidental, Venezuela and as Lecturer in the Biology Department at the University of San Diego, California.
Education and Training
Postdoctoral training (Pew Fellow/Research Associate) The Salk Institute, California
PhD in Pharmacology University College London (University of London), England
Veterinarian (D.V.M.) Universidad Centroccidental Lisandro Alvarado, Venezuela
Honors and Recognition
Pew Fellow in the Biomedical Sciences
Related Disease
Aging-Related Diseases, Alzheimer’s Disease, Brain Injury, Epilepsy, Molecular Biology, Nervous System Injury, Neurodegenerative and Neuromuscular Diseases, Neurological and Psychiatric Disorders, Parkinson’s Disease, Stroke, Traumatic Injury
Phenomena or Processes
Aging, Apoptosis and Cell Death, Calcium Signaling, Cell Biology, Cell Signaling, Cell Surface Receptors, Development of Neuronal Circuits, Disease Therapies, Neurobiology, Neurogenesis, Neuron-Glia Interactions in Myelin, Neurotransmitters, Synapse Function, Synaptic Transmission
Anatomical Systems and Sites
Brain, General Cell Biology, Nervous System
Research Models
Cultured Cell Lines, Human Cell Lines, Human Embryonic Stem Cells, Mouse, Mouse Cell Lines, Primary Cells, Primary Human Cells, Rat, Vertebrates, Xenopus
Techniques and Technologies
Biophysics, Biophysiology, Calcium Imaging, Cellular and Molecular Imaging, Electrophysiology, Fluorescence Microscopy, Ion Channels, Live Cell Imaging, Mouse Behavioral Analysis, Pharmacology, Transplantation
Working on basic neuroscience discovery research. I use cellular and animal models of neurodegeneration to identify basic disease-causing mechanisms and disease-relevant targets involved in abnormal neuron-glia signaling, synapse failure, neuronal network dysfunction and neuronal loss in age-related neurodegenerative diseases; including Alzheimer’s and Parkinson’s disease. Extensive hands-on experience working and managing projects that require a strong background in in-vitro, ex-vivo and in-vivo neuroscience, pharmacology and electrophysiology.
Barbara Ranscht earned her PhD in Cell Biology/Developmental Neurobiology from the University of Tübingen, Germany in 1981. Her postdoctoral training was at King’s College in London, U.K., and the Massachusetts Institute of Technology in Cambridge, Massachusetts. Dr. Ranscht joined Sanford Burnham Prebys in 1987, and holds an adjunct professorship in the Department of Neurosciences at University of California, San Diego. From 1989 to 1992, Dr. Ranscht was the recipient of a McKnight Scholarship.
Education
1981: PhD, University of Tübingen, Germany Neurobiology
Related Disease
Attention-deficit hyperactivity disorder (ADHD), Cancer, Cardiovascular Diseases, Metabolic Syndrome, Multiple Sclerosis, Neurological and Psychiatric Disorders
Our lab studies cell surface interactions that regulate signaling networks in the nervous and cardiovascular systems and in cancer. With focus on the brain, we investigate membrane glycoproteins that enable crosstalk of neurons with the environment during circuitry development and disease. Our group has contributed seminal insights into the functions of Contactin-1 (Cntn1) and T-cadherin (Cdh13) in axon guidance, synapse formation and myelination using knock-out mouse models as well as biochemical, electrophysiological, histological and cellular approaches. Our current work explores the role of T-cadherin in brain circuitries enabling learning and memory formation, and determines how Contactin-1 functions in processes of myelination and remyelination. Exploiting our mouse genetic model, we uncovered a novel function for T-cadherin in protecting against stress-induced cardiac injury, and revealed disruptions of T-cadherin-mediated cellular interactions in cancer. In these latter contexts, our research identified T-cadherin as a major receptor for Adiponectin (Adipoq), a fat-secreted, circulating hormone that is of high clinical interest for its role in positively regulating energy balance and protecting against cellular insult. Current work in the lab aims to understand the molecular processes and signaling pathways regulated by T-cadherin or Contactin-1 in nervous system, cardiovascular and cancer functions with the goal to derive translational applications.
Barbara Ranscht’s Research Report
Functions of T-cadherin/Cdh13 in Neuronal Circuits Involved in Learning and Memory
Cell adhesion molecules play seminal roles in synapse formation, stability and function in the central nervous system (CNS). T-cadherin (Cadherin-13; Cdh13), a glycosylphosphatidylinositol-linked cadherin-type cell adhesion molecule discovered in our laboratory, is prominent in diverse structures of the CNS. Mutations in the human CDH13 gene are linked to neuropsychiatric disorders, most prominently Attention Deficit Hyperactivity Disorders and its comorbidities. Our lab generated mice deficient for T-cadherin gene expression (Tcad-KO) mice to uncover the T-cadherin-dependent neuronal circuitries and probe its contribution to cognitive function. Tcad-KO mice show no overt developmental, neurological or sensory deficiencies, and are indistinguishable from wild type littermates under normal housing conditions. However, challenging the mice in behavioral tests revealed defects in performing select learning tasks. Investigating hippocampal circuitry as a central relay station for learning and memory, we identified reductions in CA1 synaptic transmission and long-term potentiation along with reduced spine densities and maturation of hippocampal pyramidal neurons. Current work aims to link T-cadherin to specific synaptic circuitry, and probe its function through conditional T-cadherin ablation in select neuron populations of the interconnected circuitry to contribute principal understanding to human cognitive disorders.
Mechanisms of Myelination and Remyelination
Myelin, a multilayered membrane sheath formed by oligodendrocytes around axons in the central nervous system (CNS) enables rapid nerve impulse conduction and sustains neuronal health and survival. Our lab is interested in the signals exchanged between axons oligodendrocytes during myelin formation and repair. Contactin-1, a GPI-linked cell surface glycoprotein, studied in our lab has emerged as one of the critical proteins to regulate axon-glia communication. In peripheral myelinated nerves, Contactin is solely expressed by neurons, and together with Caspr clusters at the paranodal axon domain to orchestrate formation of the septate-like axoglial junctions. In the CNS, Contactin delineates paranodes and nodes of Ranvier in mature myelin, and oligodendrocytes during the process of active myelination. We recently documented a vital dual role of Contactin-1 in central myelin formation: Contactin-mediated interactions between axons and oligodendrocytes regulate the extension and wrapping of myelin membranes, and loss of these interactions leads to hypomyelination in the mouse knockout model. The residual myelin is non-functional due to disrupted paranodal junctions that are characterized by loss of Contactin-associated paranodal Caspr, mislocalized potassium channels and disrupted transverse bands. Current work in the lab investigates the distinct contributions of Contactin in neurons and oligodendrocytes in mice with conditional Contactin-1 deletion, myelinating co-cultures and mouse models of myelin injury. If indicated, this work will form the basis for translational aspects of myelin repair.
Adiponectin – T-cadherin/Cdh13 Signaling in Cardioprotection
Adiponectin is of significant clinical interest for its potency in counterbalancing the adverse effects of obesity-linked metabolic disease and cardiovascular dysfunctions. Research in the field is increasingly focusing on local actions of APN in its target tissues where binding to the cell surface leads to activation of intracellular signal transduction pathways that increase cellular energy and counteract adverse processes such as generation of reactive oxygen species, misbalanced cellular metabolism, and apoptotic cell death. Our lab identified T-cadherin as a major ligand-binding receptor for Adiponectin in the cardiovascular system (Denzel et al, 2010). T-cadherin effectively sequesters APN from serum and its absence leads to excessive APN concentrations in the circulation. Under cardiac stress, induced by pressure overload, T-cadherin is necessary to confer cardioprotection through APN. Downstream, APN engagement with T-cadherin activates the AMP-activated protein kinase (AMPK), a major downstream signaling target of APN. Since T-cadherin is a GPI-linked cell surface glycoprotein lacking the cytoplasmic region, it is our working model that T-cadherin connects through associated molecules to intracellular signaling pathways. We are exploring the heptahelical APN-receptors AdipR1/R2 as prime candidates while considering alternative possibilities. Combining our cellular and functional analyses of T-cadherin with the extensive expertise in heart function at our Institute, we hope to make headway in determining APN-associated signaling pathways involving T-cadherin and AdipoR receptors. This work will fill the current knowledge gap of understanding APN interactions with its target cells in the cardiovascular system and may aid the development of novel molecular approaches for cardioprotection.
T-cadherin/Cdh13 in Cancer
T-cadherin has also emerged as one of the key molecules altered in diverse types of cancer. Epithelial-mesenchymal transition (EMT) during neoplasia is characterized by the down-regulation of T-cadherin/CDH13, and this silencing is linked to increased proliferative and invasive potential of human cancers. We used the mouse genetic model to investigate functions of T-cadherin in tumors. In the mouse mammary tumor virus-driven polyoma middle T (MMTV-PyV-mT) model, T-cadherin is down-regulated from neoplastic epithelial cells while it is upregulated in the tumor vasculature. Under conditions of T-cadherin deficiency, MMTV-PyV-mT induced tumor growth occurs with delayed onset and at reduced growth rates that result in prolonged animal survival over non-mutant mice. Our analyses identified reduced tumor vascularization as the major underlying mechanism for this beneficial outcome. T-cadherin’s pro-angiogenic role is mediated by the association of Adiponectin: The APN-deficient MMTV-PyV-mT tumor phenotype mirrors the defects in T-cadherin knockout mice, and in vitro silencing of T-cadherin in endothelial cells abrogates the cellular responses to APN. Our lab is now interested in understanding the mechanism by which T-cadherin binding to Adiponectin affects endothelial cell function and develop strategies to control tumor angiogenesis.
Douglas Sheffler studies the many facets of addiction, including addiction to the nicotine found in tobacco products. Smoking continues to be the leading cause of preventable deaths in the United States, and the second leading cause of preventable deaths worldwide after hypertension (of which smoking is a risk factor).
With Peter Cosford, PhD, Sheffler, in collaboration with colleagues at UC San Diego and Camino Pharma LLC, a San Diego-based biotechnology company Cosford co-founded, are conducting clinical trials to advance an investigational drug called SBP-9330.
SBP-9330 targets a neuronal signaling pathway that underlies addictive behaviors, including tobacco use. If ultimately approved for market, it would be a first-in-class oral therapeutic to help people quit smoking.
“Our research suggests that SBP-9330’s mechanism of action—how it works—may also be effective for other types of addiction, such as cocaine, opioid and methamphetamine. In the future, we hope to explore and broaden the drug’s therapeutic uses.”
Prior to coming to Sanford Burnham Prebys in 2012 as a research assistant professor, Sheffler served in the same capacity at Vanderbilt University. He earned his PhD in biochemistry from Case Western Reserve University and his Bachelor of Science degree from Saint Vincent College.
2013 NARSAD Young Investigator Award Brain and Behavior Research Foundation
Related Disease
Alzheimer’s Disease, Huntington’s Disease, Neurodegenerative and Neuromuscular Diseases, Neurological and Psychiatric Disorders, Schizophrenia
Dr. Sheffler joined the Sanford Burnham Prebys faculty in September 2012. Prior to this, he was a Research Assistant Professor at Vanderbilt University in the laboratory of P. Jeffrey Conn (2010-2012), where he also performed post-doctoral work (2006-2010). Dr. Sheffler has over 15 years’ experience in the study of G-protein coupled receptor (GPCR) signaling, assay development, high throughput screening for novel GPCR ligands, cell biology, neuroscience, and pharmacology. His interests are in the complex regulation of GPCRs: their signal transduction, ligand binding, receptor desensitization, and the processes of GPCR internalization and down-regulation. In addition, he has also has a specific interest in both the pharmacology of GPCRs, in general mechanisms of signal transduction, and in the pathogenesis of schizophrenia. During his graduate studies at Case Western Reserve University in the laboratory of Bryan L. Roth, MD, PhD, he discovered the regulation of 5-HT2A serotonin receptor signal transduction by p90 ribosomal S6 kinase (RSK2). During his post-doctoral studies and work as a Research Assistant Professor at Vanderbilt University, he focused on the discovery and characterization of orthosteric and allosteric modulators of GPCRs and led pharmacology efforts characterizing novel M1 muscarinic acetylcholine receptor agonists and antagonists, M1 positive allosteric modulators (PAMs), Glycine Transporter Type 1 (GlyT1) inhibitors, and novel Group II metabotropic glutamate receptor (mGlu) PAMs and NAMs. Dr. Sheffler’s research has resulted in more than 45 journal articles and is a listed inventor on five patent applications pertaining to small molecule therapeutics. Dr. Sheffler received a NARSAD Young Investigator Award in 2013 from the Brain and Behavior Research Foundation.
Douglas Sheffler’s Research Report
The metabotropic glutamate receptors (mGlus) are G protein-coupled receptors (GPCRs) that play numerous roles in modulating synaptic transmission and cell excitability. Recent preclinical and clinical studies provide strong evidence that agonists of the group II mGlus, comprised of the mGlu2 and mGlu3 subtypes, may provide a novel approach to treatment of schizophrenia and anxiety disorders. Based on this, there has been a major focus on understanding the roles of these receptors in regulating transmission in forebrain and limbic circuits. However, currently available orthosteric (glutamate site) agonists activate both mGlu2 and mGlu3 and do not provide insight into which subtype is most important for clinical efficacy. Alternatively, recent focus on compounds interacting with less highly conserved allosteric sites has led to advances in subtype selective compound development. Dr. Sheffler and others have discovered and characterized highly selective mGlu2 positive allosteric modulators (PAMs), that have no effect on mGlu3, and these compounds have allowed us to elucidate many of the physiological roles of mGlu2. These PAMs do not activate the receptor directly but act allosterically to potentiate glutamate responses. Dr. Sheffler and collaborators have also discovered group II mGlu negative allosteric modulators (NAMs) and have very recently discovered the first highly selective antagonist of mGlu3. The development of these pharmacological tools provides an opportunity to fully elucidate the roles of these mGlu subtypes. The group II mGlus play important roles in regulating transmission through the hippocampal formation. For example, activation of presynaptic group II mGlus reduces transmission at numerous hippocampal synapses including perforant path-dentate gyrus synapses and the mossy fiber synapse. In contrast, presynaptic group II mGlus are not involved in directly regulating transmission at the Schaffer collateral – CA1 (SC-CA1) synapse. However, we have previously reported extensive studies demonstrating group II mGlu involvement in a novel form of glial-neuronal communication in hippocampal area CA1. When coincidentally activated with β-adrenergic receptors (βARs) in astrocytes, group II mGlus induce a marked potentiation of cAMP responses elicited by activation of βARs. This synergistic increase in glial cAMP accumulation results in the release of adenosine, which activates presynaptic A1 adenosine receptors on neighboring SC terminals and induces a profound depression of transmission at the SC-CA1 synapse. This novel form of glial-neuronal signaling may provide a protective mechanism to reduce the risk of excitotoxicity when there is excessive excitatory drive to the hippocampus, such as during periods of intense or prolonged stress. This potential role has implications relevant for the therapeutic effects of group II mGlu agonists and is consistent with multiple studies suggesting group II mGlu agonists can reduce both acute and long term responses to stress. We have postulated that this effect is mediated by mGlu3 based on heavy expression of mGlu3 in hippocampal astrocytes. However, until now, selective reagents that differentiate between mGlu2 and mGlu3 have not been available to rigorously determine the specific group II mGlu subtype involved. The long term goal of Dr. Sheffler’s research is to establish the relative roles of individual group II mGlu subtypes in mediating glial-neuronal communication and modulating synaptic transmission in the hippocampus using pharmacological, biochemical, and electrophysiological approaches.
Evan Y. Snyder earned his MD and PhD (in neuroscience) from the University of Pennsylvania in 1980 as a member of NIH’s Medical Scientist Training Program (MSTP). He had also studied psychology and linguistics at the University of Oxford. After moving to Boston in 1980, he completed residencies in pediatrics and neurology as well as a clinical fellowship in Neonatal-Perinatal Medicine at Children’s Hospital-Boston, Harvard Medical School. He also served as Chief Resident in Medicine (1984-1985) and Chief Resident in Neurology (1987) at Children’s Hospital-Boston. In 1989, he became an attending physician in the Department of Pediatrics (Division of Newborn Medicine) and Department of Neurology at Children’s Hospital-Boston, Harvard Medical School. From 1985-1991, concurrent with his clinical activities, he conducted postdoctoral research as a fellow in the Department of Genetics, Harvard Medical School. In 1992, Dr. Snyder was appointed an instructor in neurology (neonatology) at Harvard Medical School and was promoted to assistant professor in 1996. He maintained lab spaces in both Children’s Hospital-Boston and at Harvard Institutes of Medicine/Beth-Israel Deaconess Medical Center. In 2003, Dr. Snyder was recruited to Sanford Burnham Prebys as Professor and Director of the Program in Stem Cell and Regenerative Biology. He then inaugurated the Stem Cell Research Center (serving as its founding director) and initiated the Southern California Stem Cell Consortium. Dr. Snyder is a Fellow of the American Academy of Pediatrics (FAAP). He also received training in Philosophy and Linguistics at Oxford University.
Related Disease
Alzheimer’s Disease, Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease), Arthritis, Brain Cancer, Brain Injury, Breast Cancer, Cancer, Childhood Diseases, Congenital Disorders of Glycosylation, HIV-Associated Dementia, Huntington’s Disease, Multiple Sclerosis, Muscular Dystrophy, Neurodegenerative and Neuromuscular Diseases, Neurological and Psychiatric Disorders, Parkinson’s Disease, Peripheral Vascular Disease, Skin Cancer and Melanoma, Spinal Cord Injury, Stroke, Traumatic Injury
We believe the study of stem cell biology will provide insights into many areas: developmental biology, homeostasis in the normal adult, and recovery from injury. Indeed, past and current research has already produced data in these areas that would have been difficult or impossible via any other vehicle. We have engaged in a multidisciplinary approach, simultaneously exploring the basic biology of stem cells, their role throughout the lifetime of an individual, as well as their therapeutic potential. Taken together, these bodies of knowledge will glean the greatest benefit for scientists and, most importantly, for patients. All of our research to date has been preformed in animal models with the ultimate goal of bringing them to clinical trials as soon as possible. Stem cells offer an intriguing mix of controversy, discovery, and hope. Politicians are charged with dealing with the controversial facets of stem cells, as we prefer to focus our energy on their potential for discovery and hope.
The Snyder Lab studies stem cell biology, with the goal of understanding normal development, tissue homeostasis, and recovery from injury and disease. A major focus is neural stem cells (NSCs), which can self-renew and differentiate into neurons, astrocytes, and oligodendrocytes. These properties make NSCs ideal for repair of damage due to injury or disease, but they also make them susceptible to transformation into malignant cancers.
Nicholas Cosford, PhD has served on the Sanford Burnham Prebys Board of Trustees since 2023. He is the first faculty member to do so.
Cosford joined the Sanford Burnham Prebys faculty in 2008 as an associate professor. In 2013, he became a full professor. His lab investigates the interactions of small molecule compounds with therapeutically important proteins and cellular signaling pathways. With a specific focus on the discovery and optimization of compounds that might treat cancer, central nervous system diseases and infectious diseases.
Prior to joining Sanford Burnham Prebys in 2005, Cosford worked in both the biotechnology and pharmaceutical industries. At Sibia Neurosciences and at Merck Research Laboratories, he directed multidisciplinary research teams focused on small-molecule hit-to-lead optimization and was responsible for moving several lead compounds through to the clinical phase, including a nicotinic agonist (Altinicline) from research to Phase II clinical trials for treating Parkinson’s disease.
He is an author of more than 90 peer-reviewed, published scientific papers, and has been issued more than 40 issued patents, with an additional 40 patent applications pending.
Cosford has a Bachelor of Science degree in chemistry from the University of Bath in England and Doctor of Philosophy degree in organic chemistry from Emory University in Atlanta, GA.
Related Disease
Alzheimer’s Disease, Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease), Bone Mineralization Disorders, Breast Cancer, Cancer, Neurodegenerative and Neuromuscular Diseases, Neurological and Psychiatric Disorders, Ovarian Cancer, Pancreatic Cancer, Prostate Cancer
We are interested in investigating the interactions of small molecule compounds with therapeutically important proteins and cellular signaling pathways. One aspect of our research emphasizes the use of medicinal chemistry and chemical biology approaches to probe intracellular pathways that regulate cell survival and cell growth. Another area of active research is the development of synthetic chemistry methodology using microfluidic technology for the rapid synthesis of biologically active small molecules. Therapeutically, we are primarily focused on the discovery and optimization of compounds that have the potential to treat cancer, CNS diseases and infectious diseases.
Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, Lou HJ, Raveendra-Panickar D, Yang CC, Sheffler DJ, Teriete P, Asara JM, Turk BE, Cosford ND, Shaw RJ