Personal History:2011-present: Joined the Department of Biochemistry and Molecular Biology and the Center for Biomolecular Therapeutics in July 2011
2003-2011: Associate Professor of Veterinary Pathobiology, Texas A&M University, College Station, TX, and Scientific Director of the Genetically Engineered Mouse Facility within the Texas A&M System
1989-2003: Promoted through the academic ranks at the University of South Alabama College of Medicine, Mobile, AL, to Associate Professor of Pharmacology (with tenure) and Director of the Transgenic Animal and ES Cell Core Facility
1987-1989: Research Assistant Professor, Department of Cell Biology, Vanderbilt University, Nashville, TN
1985-1987: Postdoctoral Fellow, Howard Hughes Medical Institute, Vanderbilt University, Nashville, TN. Advisor, Dr. Linda J. Van Eldik
1983-1985: Postdoctoral Fellow, Department of Cell Biology, Baylor College of Medicine, Houston, TX. Advisor, Dr. Norton B. Gilula
1978-1983: Ph.D., Baylor College of Medicine, Department of Cell Biology, Houston, TX. Advisor, Dr. Margaret Ann Goldstein; Dissertation title: "Alpha-actinin is a component of the axial filaments of the Z-lattice in striated muscle".
1974-1978: B.A. Biochemistry , Rice University, Houston, TX
Research Interests:All of our mental and physical activities require calcium (Ca2+), a ubiquitous second messenger. Nonetheless, individual cells can transduce identical changes in intracellular Ca2+ levels into unique biological responses. And, altered Ca2+ signaling is an underlying cause of many diseases. The long-term goal of our research is to develop pharmacological approaches that will prevent the transduction of aberrant Ca2+ signals into pathology. The 21 members of the S100 family of Ca2+ binding proteins play a key role in the generation of cell-type specific responses to changes in Ca2+ levels. Furthermore, alterations in S100 signaling have dramatic effects on disease pathology. Currently, we are developing pharmacological strategies that can be used to inhibit the detrimental gain of S100 function that occurs in neurological diseases and cancers.
S100-Signaling in Neurological Diseases:
Mapping the expression pattern for as well as delineating the components/function of the S100A1-signal transduction cascade in the developing, adult, aging and diseased CNS is an active area of research. Using an S100A1-LacZ reporter gene mouse model developed in our lab, we identified GABAergic interneurons as primary site of S100A1 expression in the normal brain. Phenotypic characterization of this model revealed that S100A1 regulates cerebellar volume and odor sensitivity. These phenotypic changes are likely attributable to S100A1 regulation of neuronal cell proliferation, dendrite formation, microtubule assembly, Ca2+ homeostasis, Akt phosphorylation, amyloid precursor protein expression and/or susceptibility to the neurotoxic Aï¢ peptide in Alzheimer's disease. In fact, S100A1 and another member of the S100 family, S100B, have been validated as novel drug targets for Alzheimer's disease therapy. Inhibition of S100A1 and/or S100B (genetic ablation, immunotherapy or small molecule "leads") restores cognitive function, reduces inflammation, delays plaque deposition and ameliorates increases in pathology in response to injury and environmental toxins. The discovery and development of "S100 inhibitors" that can be used to restore cognitive function in AD patients is high priority.
S100-Signaling in Cancer:
S100B binds to the tumor suppressor p53, dissociates the p53 tetramer, promotes p53 degradation, and inhibits p53 function. Inhibiting the S100B-p53 complex, on the other hand, restores p53 protein levels as well as its transcriptional and apoptotic activities. Our laboratory is using pre-clinical animal models to assess the in vivo efficacy and toxicity of lead compounds developed by Dr. David Weber's group (University of Maryland School of Medicine). A clinical trial for two FDA-approved S100B inhibitors in canine melanoma is ongoing in collaboration with Dr. Heather Wilson (Small Animal Oncology, Texas A&M University College of Veterinary Medicine).
Lab Techniques and Equipment:Our laboratory uses biochemical, cellular, molecular, pharmacological and genetic approaches/techniques to study S100 signaling. This includes the design and development of genetically modified cell lines, gene-targeted ES cells and transgenic/gene-targeted rodent models of human diseases. As part of the In Vivo Biology and Drug Testing Program within the Center for Biomolecular Therapeutics we evaluate the pharmacodynamic and pharmacokinetic profiles of lead compounds from drug discovery efforts in pre-clinical animal models.
Roltsch E R, Holcomb L, Young K, Marks A, Zimmer D B. 2010. PSAPP Mice exhibit regionally selective reductions in gliosis and plaque deposition in response to S100B ablation. J. Neuroinflam. 7:78.