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.
Johnson VE, Stewart W, Weber MT, Cullen DK, Siman R, Smith DH: SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury. Acta Neuropathologica 131(1): 115-135, Jan 2016.
Siman R, Cocca R, Dong Y.: The mTOR inhibitor rapamycin mitigates perforant pathway neurodegeneration and synapse loss in a mouse model of earl-stage Alzheimer-type tauopathy. PLoS One 10(11): e0142340, Nov 2015.
Siman R, Shahim P, Tegner Y, Blennow K, Zetterberg H, Smith DH.: Serum SNTF increases in concussed professional ice hockey players and relates to the severity of post-concussion symptoms. Journal of Neurotrauma 32(17): 1294-300, Sep 2015.
Siman R, Giovannone N, Hanten G, Wilde EA, McCauley SR, Hunter JV, Li X, Levin HS, Smith DH.: Evidence That the Blood Biomarker SNTF Predicts Brain Imaging Changes and Persistent Cognitive Dysfunction in Mild TBI Patients. Frontiers In Neurology 4: 190, Nov 2013 Notes: eCollection2013; doi: 10.3389/fneur.2013.00190.
Siman R, Lin Y-G, Malthankar-Phatak G, Dong Y.: A rapid gene delivery-based mouse model for early stage Alzheimer tauopathy. Journal of Neuropathology and Experimental Neurology 72(11): 1062-1071, Nov 2013.
Malthankar-Phatak, G., Poplawski, S., Toraskar, N. and Siman, R.: Combination therapy prevents amyloid-dependent and -independent brain structural changes. Neurobiol Aging 33(7): 1273-1283, Jul 2012.
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(5): 793-805, Jun 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.
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.
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Last updated: 01/09/2017
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