Our laboratory is interested in identifying novel targets for treating osteoporosis and cerebral ischemic stroke and thereby improve the decreased quality of life associated with aging.
Osteoporosis currently affects approximately 10 million Americans; another 34 million are osteopenic. A direct consequence of bone fragility is an increased risk of painful fractures leading to functional disabilities, increased mortality at older ages, and a huge cost burden on families and health providers. Current treatment of osteoporotic patients mostly involves fracture prevention; there are few viable treatments after fractures have occurred. Therefore, an understanding of the molecular and cellular mechanisms underlying osteoporosis and subsequent development of novel therapies are required. We have recently demonstrated that loss of caspase-2, a cysteine-aspartate protease, results in increased bone porosity. We have generated transgenic and conditional null models of caspase-2 to better understand caspase-2 function in bone. Our long-term goal is to determine the feasibility of targeting caspase-2 for improving bone mass and bone quality.
Cerebral ischemic stroke (CIS) accounts for 87% of all strokes and is the third leading cause of death in the United States, with 1 death occurring every 4 minutes. The only FDA-approved treatment for ischemic strokes is recombinant tissue plasminogen activator (tPA) that dissolves the clot; however, tPA, which can itself cause bleeding and is contra-indicated in hemorrhagic stroke, has to be administered within 3-4.5 hours after a stroke for possible recovery. Indeed, less than 2% of patients can receive tPA. Therefore, identification of new molecular players that enhance stroke recovery are urgently needed. We find that caspase-2 plays an important role in regulating stroke pathology by inhibiting autophagy and we are pursuing novel treatment modalities based on this finding.
Sharma R, Williams PJ, Gupta A, McCluskey B, Bhaskaran S, Muñoz S, Oyajobi BO. (2015) A dominant-negative F-box deleted mutant of E3 ubiquitin ligase, β-TrCP1/FWD1, markedly reduces myeloma cell growth and survival in mice. Oncotarget. Aug 28;6(25):21589-602.
Sharma R, Callaway D, Vanegas D, Bendele M, Lopez-Cruzan M, Horn D, Guda T, Fajardo R, Abboud-Werner S, Herman B. (2014) Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. PLoS One. Apr 1;9(4):e93696.
Sharma R, Gow A. (2007) Minimal role for caspase 12 in the unfolded protein response in oligodendrocytes in vivo. J Neurochem. May;101(4):889-97.
Lopez-Cruzan M, Sharma R*, Tiwari M, Karbach S, Holstein D, Martin CR, Lechleiter JD, Herman B. (2016)Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment.Cell Death Discov. Feb 15;2. pii: 16005. *Corresponding author
Branch SY, Sharma R, Beckstead MJ. (2014) Aging decreases L-type calcium channel currents and pacemaker firing fidelity in substantia nigra dopamine neurons. J Neurosci. Jul 9;34(28):9310-8.
Sharma R, Tsuchiya M, Skobe Z, Tannous BA, Bartlett JD. (2010) The acid test of fluoride: how pH modulates toxicity. PLoS One. May 28;5(5):e10895.
Sharma R, Tsuchiya M, Bartlett JD. (2008) Fluoride induces endoplasmic reticulum stress and inhibits protein synthesis and secretion. Environ Health Perspect. Sep;116(9):1142-6.
Sharma R, Jiang H, Zhong L, Tseng J, Gow A. (2007) Minimal role for activating transcription factor 3 in the oligodendrocyte unfolded protein response in vivo. J Neurochem. Sep;102(5):1703-12.
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