Dr. Layton Smith is the Director of Drug Discovery and Exploratory Pharmacology for the Conrad Prebys Center for Chemical Genomics (Prebys Center) at Sanford Burnham Prebys Medical Discovery Institute at Lake Nona (SBP). He is also the Principal Investigator for the Florida Translational Research Program at SBP, Florida’s state-funded program for drug discovery.
Prior to joining Sanford Burnham Prebys, Layton was the Associate Director of Pharmacology at The Scripps Research Institute where he led the in vitro ADME/T and in vivo DMPK teams in support of several discovery projects spanning oncology, diabetes, and vascular diseases. After moving to SBP, he established a Pharmacology core facility to complement the small molecule discovery platforms already in existence. In 2009, Layton was promoted to Director of Drug Discovery. Since then, he has been involved in center leadership, strategic planning, and in the coordination of effort between the project teams of the Center and its collaborators to execute projects on schedule and on budget.
Layton received his doctorate degree (Pharmacology, 2002) from Vanderbilt University, Nashville, Tennessee, where he also received his postdoctoral training in Clinical Pharmacology and Cardiovascular Medicine.
Related Disease
Atherosclerosis, Cardiovascular Diseases, Hypertension, Metabolic Syndrome
Dr. Layton Smithhas extensive training in both experimental and clinical pharmacology, and during the last six years has worked on numerous collaborative research projects as part of the PrebysCenter’s efforts to reimagine the early drug discovery process and find innovative new medicines based upon discoveries made in university research labs across the US.
The Smith lab focuses on identifying molecular mechanisms of increased risk for cardiovascular disease in the metabolic syndrome, by studying apelin, a vasoactive peptide that increases cardiac contractility and decreases vascular tone to reduce blood pressure. Paradoxically, this vasoprotective peptide is over-produced by fat in obese people, but fails to elicit the positive effects on the cardiovascular system. To address this paradoxical effect, Smith employs molecular biology, cellular and animal models, novel pharmacologic tools and is currently developing cell-based assays to identify small molecule probes of the apelin receptor using an HTS strategy.
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.
Figure 1: T-cadherin expression in adult hippocampus. T-cadherin staining delineates the dendritic layer of pyramidal neurons in CA1-CA3 subfields, and the molecular layer in the dentate gyrus. Staining is absent from the hippocampus of Tcad-KO mice. NeuN outlines the positions of pyramidal and granule neurons for orientation. Images by Hedie Badieh-Madhavi, PhD and Jinsha Liu, graduate student.
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.
Figure 2: In mouse P10 optic nerve, Ccntactin (green) delineates oligodendrocyte progenitor cells demarcated by NG2 (red). Staining for Contactin does not overlap with APC (blue), a marker for mature oligodendrocytes. Image by Gulsen Colakoglu, PhD
Figure 3: In mice deficient for Contactin-1, loss of axon-glia cross-talk leads to hypomyelination. Shown here are electron micropgraphs from P17 wildype and knockout (KO) optic nerves. Images Erik O. Berglund, MD, PhD
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.
Figure 4: T-cadherin requirement in reverting exaggerated cardiac hypertrophy in APN-KO mice. Trichorme-stained hearts (left) show cardiac hypertrophy induced by pressure overload. Hypertrophy can be reverted in Adiponectin knockout (APN KO) mice by adenovirus-mediated expression of recombinant Adiponectin (adAPN; upper panel). In the absence of T-cadherin, APN-KO cardiac tissue does not respond (upper panel). Control virus expressing green fluorescent protein (adGFP) has no effect on the heart hypertrophic phenotype (lower panels). Mechanistically, as shown by immunohistochemistry, low T-cadherin expression in APN-KO hearts (Tcad, green, lower panel) is upreguated by adAPN (Tcad, green, upper panel) and binds adAPN which triggers downstream cardioprotective pathways. Data by Martin Denzel, PhD
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.
Figure 5: T-cadherin in the neoplastic mammary gland. A. In early stage MMTV-PyV-mT mouse tumors, T-cadherin (green) and E-cadherin (red) are down-regulated from developing neoplasias (a-c; central white box magnified as insert) while both cadherins are expressed on the non-cancerous ductal epithelium (white arrows in a-c), Histology shows the pathology of a normal duct (asterisk) and developing neoplasias (d, black arrows; scale bars 50 mm). In developed MMTV-PyV-mT tumors, T-cadherin (green in e) is upregulated on the CD31-positive tumor vasculature (f and g). The pathology of a MMTV-PyV-mT tumor is shown in f. B, T-cadherin is detected as a protein doublet of 95 kD and 115kD by Western blotting of normal mouse mammary fat pads and is down-regulated in the neoplastic mammary gland. Beta tubulin Is used as a gel loading control. No T-cadherin protein is detected in the T-cadherin-deficient (KO) MMTV-PyV-mT tumors. Data by Lionel Hebbard, PhD
Related Disease
Cardiomyopathies, Cardiovascular Diseases
Anatomical Systems and Sites
Cardiovascular System, General Cell Biology, Heart
Research Models
Computational Modeling, Drosophila, Human
Techniques and Technologies
Bioinformatics, Cell Biology, Confocal Microscopy, Fluorescence Microscopy, Genetics, In vivo Modeling, Live Cell Imaging, Live Imaging, Microscopy and Imaging, Molecular Biology, RNA Interference (RNAi), Systems Biology, Transgenic Organisms
Dr. Tautz develops novel drugs targeting protein tyrosine phosphatases that are implicated in cancer, thrombosis, and Alzheimer’s disease.
Dr. Tautz earned his PhD in Organic Chemistry and Biochemistry from the University of Karlsruhe (Germany) with Dr. Janos Retey in 2002. He continued his research at the Burnham Institute with Dr. Tomas Mustelin, first as a postdoc and later as a staff scientist. In 2009 Dr. Tautz joined the faculty of the Sanford Burnham Prebys Medical Discovery Institute.
Education
2002: PhD, University of Karlsruhe, Germany, Chemistry, Biochemistry 1997: MS, University of Karlsruhe, Germany, Chemistry
Funding Awards and Collaborative Grants
American Heart Association Innovative Research Grant
Honors and Recognition
2014: Semifinalist, Stadtman Investigator Search, National Institutes of Health 2008/2006 : Society for Biomolecular Sciences Travel Awards 2006: American Chemical Society Travel Award 2006: William and Lillian Fishman Award for Exceptional Postdoctoral Research 2002: PhD in Chemistry magna cum laude, University of Karlsruhe, Germany
Related Disease
Alzheimer’s Disease, Cancer, Cardiovascular Diseases, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma, Neurodegenerative and Neuromuscular Diseases
Many human diseases stem from abnormalities in the activities of protein kinases and protein phosphatases. While efficacious therapeutics targeting protein kinases have been successfully used in the clinic (e.g., Gleevec), effective strategies to target specific protein phosphatases are still elusive. Dr. Tautz’ laboratory works on novel, more effective approaches to target these important enzymes. He focuses on protein tyrosine phosphatases implicated in cancer, thrombosis, autoimmunity, and Alzheimer’s disease.
Lutz Tautz’s Research Report
1. Discovery of a Novel Drug Target in Arterial Thrombosis
Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. In collaboration with researchers at the University of Liege in Belgium (Drs. Souad Rahmouni and Cecile Oury), we recently identified DUSP3 (also known as VHR) as a major regulator in platelet signaling and thrombosis. Intriguingly, bleeding was not affected by DUSP3 deficiency in mice, suggesting that DUSP3 plays a key role in arterial thrombosis, but is dispensable for primary hemostasis. We develop a specific small-molecule inhibitor of DUSP3 that effectively inhibited platelet aggregation in human platelets, thereby phenocopying the effect of DUSP3 deficiency in murine platelets. We are now poised to optimize this compound for in vivo studies in order to provide proof-of-concept for a novel and potentially safer antiplatelet strategy based on DUSP3.
2. Discovery of a Novel Mechanism in T Cell Activation
PTPs are crucial for maintaining the homeostasis of the immune system, including the regulation of antigen receptor-mediated lymphocyte activation and cytokine-induced differentiation. The lymphoid tyrosine phosphatase (LYP, PTPN22) is a critical negative regulator of T cell antigen receptor signaling. A single-nucleotide polymorphism (SNP) in PTPN22 was shown to correlate with the incidence of various autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. First, we helped to demonstrate that the disease-associated allele is a gain-of-function mutant, i.e. a better inhibitor of T cell receptor activation. Then, we developed a specific chemical probe of LYP which we utilized to identify the associated mechanism that leads to increased LYP activity. In contrast to what was known from work in mice, we showed that in human cells LYP needs to dissociate from CSK in order to inhibit T cell activation. We also showed that our LYP inhibitor acts by stabilizing a unique inactive conformation of LYP.
We have been working on chemical probes for cancer targets for several years (e.g., VHR, HePTP). Currently, we focus on the role of SHP2 in leukemia and breast cancer. PTPN11, the gene encoding SHP2, has been widely recognized as an oncogene. Germline mutations in PTPN11 were first observed in ~50% of cases of Noonan syndrome, an autosomal dominant developmental disorder with increased risk of malignancy. Numerous somatic gain-of-function mutations in PTPN11 have been identified in various leukemias. Hyperactivated SHP2 was also found in several types of solid tumors, including breast cancer. Previously reported SHP2 inhibitors lack efficacy in cancer cells and/or selectivity over related homologs. Novel SHP2 antagonists are needed for proof-of-principle studies that support a therapeutic approach based on SHP2. We have identified novel SHP2 lead compounds with significantly improved efficacy and selectivity. Currently, we optimize these compounds to make them suitable for in vivo studies.
Alzheimer’s disease (AD) is characterized by a progressive loss of cognitive function. The FDA has approved four drugs to treat the cognitive deficits in AD (donepezil, galantamine, rivastigmine, and memantine). However, none of these drugs halt disease progression. Our collaborator Dr. Paul Lombroso (Yale) identified the STriatal-Enriched Phosphatase (STEP) as a novel therapeutic target involved in the initial synaptic dysfunction that occurs prior to loss of neurons. His work suggests that inhibition of STEP could provide a disease-modifying strategy and early treatment option for AD. We recently received funding from the Alzheimer’s Association to develop a high-throughput assay to screen large chemical libraries for compounds that inhibit STEP function in neuronal cells. Once such compounds are identified, we will test their potential to reverse the biochemical and cognitive defects in AD animal models.
After receiving his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, Dr. Millán first joined the La Jolla Cancer Research Foundation (LJCRF) in 1977, the predecessor of Sanford Burnham Prebys, as a trainee in clinical enzymology. He completed his PhD studies in Medical Biochemistry at the University of Umeå, Sweden and after post-doctoral stints in Copenhagen and LJCRF he was appointed to the faculty at SBP in 1986. He served as Professor of Medical Genetics in the Department of Medical Biosciences at his alma mater, Umeå University, Sweden, from 1995-2000. He was appointed Sanford Investigator at the Sanford Children’s Health Research Center at Sanford Burnham Prebys in 2008.
Honors and Recognition
2018: ASBMR Lawrence G. Raisz Award for Pre-clinical Research. 2001: Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain 1992: Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.
Related Disease
Arthritis, Bone Mineralization Disorders, Cardiovascular Diseases, Colorectal Cancer, Crohn’s Disease (Colitis), Heart Disease, Inherited Disorders, Metabolic Syndrome, Peripheral Vascular Disease, Testicular Cancer
Phenomena or Processes
Cardiovascular Biology, Disease Therapies, Extracellular Matrix, Protein Structure-Function Relationships
Anatomical Systems and Sites
Cardiovascular System, Musculoskeletal System, Vasculature
Research Models
Mouse
The Millán laboratory works on understanding the mechanisms that control normal skeletal and dental mineralization and elucidating the pathophysiological abnormalities that lead to heritable soft bones conditions such as Hypophosphatasia (HPP) and to soft-tissue calcification, including vascular calcification, that is a hallmark in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millán’s research has already contributed to the implementation of a novel therapy for HPP, a genetic disease caused by deficiency in tissue-nonspecific alkaline phosphatase (TNAP) function, that leads to accumulation in the extracellular space of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. HPP is characterized by defective mineralization of bones (rickets or osteomalacia), and teeth that display a lack of acellular cementum, hypomineralized dentin and enamel, and periodontal defects. Dr. Millán’s team has demonstrated the effectiveness of enzyme replacement therapy using mineral-targeted recombinant TNAP (asfotase alfa) to prevent the skeletal and dental defects in the TNAP knockout mouse model of infantile HPP. This therapy was approved in 2015 for the treatment of patients with pediatric-onset HPP.
Current efforts, in collaboration with Professor Miyake’s group in Japan (https://www.nms-gt.org/en/members), focus on developing gene therapy as an alternative approach to treat HPP. Dr. Millán’s group has also identified key pathophysiological changes that lead to calcification of the arteries in animal models of generalized arterial calcification of infancy, pseudoxanthoma elasticum and related genetic diseases as well as in animal models of chronic kidney disease. His group, in collaboration with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys, has developed proprietary compounds able to ameliorate the soft-tissue calcification in these conditions and clinical trials are now underway using these first-in-class small molecule inhibitors.
Dr. Colas earned his PhD from the Universite Pierre et Marie Curie, Paris, France.
Funding Awards and Collaborative Grants
2011-2013: American Heart Association Post-Doctoral Fellowship 2011: Best Talk Award (Development & Aging Post-Doctoral Retreat, SBP) 2010-2011: California Institute for Regenerative Medicine Post-Doctoral Fellowship 2006-2007: French Myopathy Association PhD Fellowship 2003-2006: Ministry of French Research PhD Fellowship 2000-2001: Erasmus Undergraduate Fellowship
Related Disease
Cardiomyopathies, Cardiovascular Diseases, Heart Disease
Phenomena or Processes
Cardiovascular Biology, Cell Biology, Development and Differentiation, Embryogenesis, Embryonic/Pluripotent Stem Cells, Regenerative Biology, RNA-Based Gene Regulation, Transcription Factors
Our laboratory focuses on the identification and reconstruction of novel regulatory pathways controlling the determination and the acquisition of cardiovascular cell fates in humans. To that end, our team has developed a unique set of cell-based assays suitable for high-throughput functional screening, which enables the implementation of unbiased and systematic experimental approaches with unprecedented exploratory power. Our goal is to leverage generated knowledge to produce better cardiomyocytes to model cardiac diseases in-a-dish as well as to devise innovative cardiac regenerative strategies. In parallel, our lab is also dedicated to identify and develop new drugs promoting cardiac regeneration and/or helping preserving heart function after injury.
Rolf Bodmer earned his PhD in Biochemistry and Neurobiology from the University of Basel, Switzerland, in 1983. Dr. Bodmer trained as a postdoctoral fellow in Neurobiology at the Albert Einstein College of Medicine in New York, and also studied Molecular Genetics at the University of California, San Francisco. He was appointed Assistant Professor of Biology in 1990 at the University of Michigan. There, he was promoted to Associate Professor of Biology in 1996, and then appointed to Associate Professor of Molecular, Cellular and Developmental Biology in 2001. Dr. Bodmer joined Sanford Burnham Prebys in 2003, where he is Professor and Program Director of the Development, Aging, and Regeneration Program.
Other Appointments
Adjunct professor, University of California, San Diego
Funding Awards and Collaborative Grants
1 P01 AG033561 “Genetic Analysis of Drosophila Functional Aging”
The Bodmer Laboratory is interested in the molecular mechanisms of organ formation, how patterns are generated and how cells and tissue types assume their correct fates and functions. The Bodmer lab is pursuing this interest by studying the genetic functions and interactions that specify heart development and maintain heart performance in the Drosophila model, in the hope of elucidating basic principles in organogenesis and functionality.
We study the HIF and Notch pathways in various organismal responses to hypoxia. Both of these pathways as well as mechanisms and responses to hypoxia are of high relevance to cancer research.
We are also studying master regulatory networks in how they control metabolism and obesity. These fundamental studies on obesity pathways will also be highly relevant to cancer metabolism.
