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Danna B Zimmer
 

Danna B Zimmer Ph.D.

Academic Title: Associate Professor
Primary Appointment: Biochemistry and Molecular Biology
dzimmer@som.umaryland.edu
Location: 108 N. Greene Street, 103

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 A 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.

Publications:

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.

Zimmer D B, Weber D J. 2010. The calcium-dependent interaction of S100B with its protein targets. Cardiovas. Psychiatry Neurol., Epub Aug 17, 2010.

Ellis G, Fang E, Maheshwari M, Roltsch E, Holcomb L, Zimmer D B, Martinez D, Murray I. 2010. Lipid oxidation and modification of Amyloid β (Aβ) in vitro and in vivo. J. Alzheimer's Disease, 22:593-607.

Prosser B L, Andronache Z, Hernandez-Ochoa E O, Zimmer D B, Lovering RM, Melzer W, Schneider M F. 2010. S100A1 promotes action potential-initiated calcium release flux and force production in skeletal muscle. Am. J. Physiol., Cell Physiol.,

Prosser B L, Hernandez-Ochoa E O, Zimmer D B, Schneider MF. 2009. Simultaneous recording of intra-membrane charge movement components and calcium release in wild type and S100A1-/- muscle fibres. J. Physiol., 587:4543-4559.

Prosser B L, Hernandez-Ochoa E O, Zimmer D B, Schneider M F. 2009. The Q{gamma} component of intra-membrane charge movement is present in mammalian muscle fibres, but suppressed in the absence of S100A1. J. Phyiol., 587:4523-4541.

Wright N T, Cannon B R, Wilder P T, Morgan M T, Varney K M, Zimmer D B, Weber D J. 2009. Solution structure of S100A1 bound to the CapZ peptide (TRTK12). J. Mol. Biol., 386:1265-1277.

Wright N T, Cannon B R, Zimmer D B, Weber, D J. 2009. S100A1: Structure, function, and therapeutic potential. Current Chem. Biology, 3:138-145.

Wright N T, Prosser B L, Varney K M, Zimmer D B, Schneider M F, Weber D J. 2008. S100A1 and calmodulin compete for the same binding site on ryanodine receptor. J. Biol. Chem., 283:26676-26683.

Prosser B L, Wright N T, Hernandez-Ochoa E, Varney K M, Liu Y, Olojo R O, Zimmer D B, Weber D J, Schneider, M F. 2008. S100A1 binds to the calmodulin binding site of ryanodine receptor and modulates skeletal muscle EC coupling. J. Biol. Chem., 283:5046-5057.

Stanfel M N, Moses K A, Carson J A, Zimmer D B, DeMayo F, Schwartz R J., Zimmer W E. 2006. Expression of an Nkx3.1-CRE gene using ROSA26 reporter mice. genesis, 44:220-555.

Zimmer D B, Chaplin J, Baldwin A, Rast M A. 2005. S100-mediated signal transduction in the nervous system and neurological diseases. Cellular Molecular Biology, 51, 201-214.

Wright N T, Varney K M, Ellis K C, Gitti R K, Zimmer D B, Weber D J. 2005. The three-dimensional solution structure of a Ca2+-bound S100A1 as determined by NMR spectroscopy. J. Mol. Biol., 353, 410-426.

Arakaki T L, Pezza J A, Cronin M A, Hopkins C E, Zimmer D B, Tolan D R, Allen K N. 2004. Structure of human brain fructose 1,6-(bis)phosphate aldolase: Linking isozyme structure with function. Protein Science, 13, 3077-3084.

Tsoporis J N, Marks A, Zimmer D B, McMahon C, Parker T G. 2003. The myocardial protein S100A1 plays a role in the maintenance of normal gene expression in the adult heart. Mol. & Cell. Biochem., 242, 27-33.

Zimmer D B#, Sadosky P, Weber D J#. 2003. Molecular mechanisms of S100-target protein interactions. Microscopy Research & Technique. 60, 552-559.

Rustandi R, Baldisseri D, Inman K, Nizner P, Hamilton S, Lander A, Landar A, Zimmer D B, Weber D. 2002. The three-dimensional solution structure of the calcium-signaling protein apo-S100A1 as determined by NMR. Biochem., 41, 788-796.

Lin J, Blake M, Tang C, Zimmer D B, Rustandi R, Weber D, Carrier F. 2001. Inhibition of p53 transcriptional activity by the S100B calcium binding protein. J. Biol. Chem., 276, 35037-35041.
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