The goal of this proposal is to advance the development of Dr. David Huang as an independent researcher who will study endogenous neuroprotective pathways and will develop novel therapeutic approaches for the treatment of stroke. Dr. Huang proposes a mentoring environment and research plan designed to strengthen his background and technical skills in biochemistry, cellular and molecular biology, stroke models and microscopy. The research plan will explore fundamental mechanisms involved in neuroprotection. Understanding such mechanisms in the setting of stroke will help to develop novel strategies for treatment and prevention of this disease. Dr. Huang will characterize the protein CHIP (carboxyl terminus of HSC70- interacting protein), a modulator of heat shock proteins (HSPs). CHIP and HSPs regulate protein turnover by working together to ubiquitinate proteins, which targets these proteins for proteasomal degradation. CHIP appears to be cytoprotective, as mice lacking CHIP were extremely sensitive to heat stress. CHIP is hypothesized to be protective in certain neurodegenerative diseases. The applicant proposes to study CHIP in the setting of cerebral ischemia. The general hypothesis to be tested is: CHIP is neuroprotective following cerebral ischemia. Dr. Huang will characterize CHIP in the nervous system. He will utilize a model of focal stroke to study the effects of cerebral ischemia in CHIP-deficient mice. He will utilize a culture model of ischemia to further clarify the properties of CHIP during ischemia.
The Specific Aims of this proposal are to:1) Characterize CHIP in the mouse brain, 2) determine if the distribution or level of expression of CHIP in the brain changes as a result of cerebral ischemia, 3) determine the effect of reduced CHIP on total infarct volume following focal cerebral ischemia, and 4) determine if the sub-cellular localization of CHIP in neurons changes as a result of cerebral ischemia, determine if nuclear CHIP is bound to chaperone proteins in the nucleus, and identify ubiquitinated proteins bound to CHIP following ischemia.
| Anderson, Lauren G; Meeker, Rick B; Poulton, Winona E et al. (2010) Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen-glucose deprivation. Cell Stress Chaperones 15:487-95 |
