Robert Siman

faculty photo
Research Professor of Neurosurgery
Member, Institute of Neurological Sciences
Member, Center for Brain Injury and Repair
Member, Institute for Translational Medicine and Therapeutics
Department: Neurosurgery

Contact information
Department of Neurosurgery
502 Stemmler Hall
36th and Hamilton Walk
Philadelphia, PA 19104
Office: 215-573-6245
Fax: 215-898-9217
Graduate Group Affiliations
Education:
B.A. (Biology)
University of Pennsylvania, 1976.
Ph.D (Neurobiology)
Northwestern University, 1981.
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Description of Research Expertise

Research Summary

Recent advances in cell biology and genetics have led to an explosion of information about intracellular signaling mechanisms for nerve cell death, and the identification of gene mutations responsible for inherited forms of many neurodegenerative diseases. There are, however, several challenges for converting these advances in basic neurobiology to new and effective treatments. Toward meeting these challenges, my laboratory is identifying specific cell death signaling pathways that underlie particular neurodegenerative processes in the brain, defining pathogenic mechanisms by which disease-causing mutations impact these signaling pathways, and devising non-invasive surrogate markers for detecting distinct modes of neurodegeneration in the brains of living organisms.

Our biomarker program has identified surrogate markers that are measurable in cerebrospinal fluid and serum following brain injury in both experimental animals and human patients, and indicate the magnitude of the brain damage, the underlying signaling mechanisms involved, and the efficacy of candidate neuroprotective treatment regimens. By developing a panel of such markers for neurodegeneration along with immunoassays for their highly sensitive and specific quantitation, we aim to impact the diagnosis, prognosis, and treatment of acute brain injuries in numerous clinical settings.

Another focus has been the characterization of mouse genetic models of Alzheimer’s disease (AD), developed either by “knocking in” disease-causing mutations in amyloid precursor protein and presenilin-1 into their endogenous mouse genes, or expressing pathological genes by a viral based approach in specific neural circuits impacted early in the course of AD. We are using the disease models to understand how an imbalance in neuronal protein homeostasis leads to abnormal protein accumulation, discern how protein aggregates impact forms of adaptive plasticity in neural pathways that are both critical for long-term memory and severely impacted in AD, and identify treatment strategies for reducing the pathology and restoring the neural plasticities.

Description of Itmat Expertise

The Siman laboratory studies the mechanisms for neurodegeneration using novel molecular genetic models in the mouse and develops protein biomarkers for brain injury with potential clinical utility as diagnostics, prognostics, and surrogate measures of neuroprotectant efficacy.

Selected Publications

von Reyn, C., Mott, R., Siman, R., Smith, D., Meaney, D.F.: Mechanisms of calpain mediated proteolysis of voltage gated sodium channel subunits following in vitro dynamic stretch injury. J Neurochem 121: 793-805, 2012.

Malthankar-Phatak G, Lin Y-G, Giovannone N, Siman R.: Amyloid deposition and advanced age fails to induce Alzheimer's-type progression in a double knock-in mouse model. Aging and Disease 2: 141-155, 2012.

Malthankar-Phatak, G., Poplawski, S., Toraskar, N. and Siman, R.: Combination therapy prevents amyloid-dependent and -independent brain structural changes. Neurobiol Aging 33: 1273-1283, 2012.

Siman R, Giovannone N, Toraskar N, Frangos S, Stein SC, Levine JM, Kumar MA: Evidence that a panel of neurodegeneration biomarkers predicts vasospasm, infarction, and outcome in aneurysmal subarachnoid hemorrhage. PLoS One Page: e28938, 2011.

von Reyn CR, Spaethling JM, Mesfin MN, Ma M, Neumar RW, Smith DH, Siman R, Meaney DF: Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit. J Neurosci 29: 10350-10356, 2009.

Siman, R., Toraskar, N., Dang, A., McNeil, E., McGarvey, M., Plaum, J., Maloney, E., Grady, M.S.: A Panel of Neuron-Enriched Proteins as Markers for Traumatic Brain Injury in Humans. J Neurotrauma 26: 1817-1827, 2009.

Siman R, Roberts VL, McNeil E, Dang A, Bavaria JE, Ramchandren S, McGarvey M.: Biomarker evidence that surgically-induced circulation arrest elicits central nervous system injury. Brain Res 1213: 1-11, 2008.

Zhang C, McNeil E, Dressler L, Siman R.: Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease. Exp Neurol 204: 77-87, 2007.

Serbest G, Burkhardt MF, Siman R, Raghupathi R, Saatman KE.: Temporal profiles of cytoskeletal protein loss following traumatic axonal injury in mice. Neurochem Res 32: 2006-2014, 2007.

DeRidder MN, Simon MJ, Siman R, Auberson YP, Raghupathi R, Meaney DF: Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition. Neurobiol Dis 22: 165-176, 2006.

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Last updated: 07/15/2013
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