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Robert Siman, Ph.D.
Res. Assoc. Professor
Department of Neurosurgery
502 Stemmler Hall
36th & Hamilton Walk
Philadelphia, PA 19104
Phone: 215-573-6245; Fax: 215-573-3803
e-mail: siman@mail.med.upenn.edu
Click here for selected publications since Dr. Siman's arrival at Penn
RESEARCH INTERESTS
RESEARCH TECHNIQUES
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. My laboratory is interested in identifying specific cell death-signaling pathways that underlie particular neurodegenerative processes in the brain, and defining the pathogenic mechanisms by which disease-causing mutations impact these signaling pathways. Our work focuses on brain proteases, which are now recognized as critical mediators of apoptotic and necrotic cell death, and the abnormal protein aggregation that is a pathological hallmark of neurodegenerative disorders.
We study (i) molecular events regulating caspases and calpains, cysteine protease families involved in apoptotic and necrotic signaling; (ii) regulation of g-secretase, the aspartic protease responsible for generating the amyloid Ab protein whose progressive accumulation is a pathological hallmark of Alzheimer's disease; (iii) protease-based markers of cell death-signaling pathways which can delineate neurodegenerativeprocesses in the brain in situ; (iv) altered proteolysis as a pathogenic mechanism in mouse genetic models of human neurodegenerative disease.
The laboratory has developed an antibody-based technology, known as protease fingerprinting, for measuring activation of specific proteases, localizing their activation at the anatomical level, and identifying their protein substrates that are potential downstream effectors of cell death signaling. Collectively, our results thus far demonstrate that cell death signaling pathways vary with cell type and toxic stimulus, and can even differ within distinct axonal and somatodendritic compartments of the neuron. This functional proteomics technology is being used now for collaborative studies examining the mechanisms underlying acute neurodegenerative processes in experimental models for cardiac arrest and traumatic brain injury. Furthermore, the recent establishment of rodent genetic models for inherited forms of chronic degenerative disorders, such as Alzheimer's (AD), Parkinson's, Huntington's diseases, Amyotrophic Lateral Sclerosis, and demyelinating disorders, has provided our laboratory with unprecedented opportunities to investigate proteolytic mechanisms involved in the pathogenesis of neurodegenerative diseases, and identify novel targets for therapeutic intervention. So far, we have exploited mouse lines bearing "knock-in" mutations in their endogenous APP and Presenilin-1 genes to elucidate how these gene defects, which cause early-onset AD in humans, lead to altered g-secretase function, Ab accumulation and neuronal activation of cell death signaling pathways in the mouse brain. We are testing the hypothesis that presenilin-1 is the catalytic component of an oligomeric g-secretase complex, and pathogenic mutations modify amyloid Ab production by altering the structure and function of the g-secretase protease complex.
