David A. Rempe, M.D., Ph.D.
Assistant Professor of Neurology
M.D. 1996, University of Virginia
Ph.D. 1997, University of Virginia

Research Interests:  Our goal is to better define the adaptive and pathological hypoxia-induced molecular mechanisms within the brain that impact tissue viability during hypoxia and stroke.

Stroke is a leading cause of death throughout the world with limited effective treatments.  Hypoxia within the stroke penumbra induces multiple molecular mechanisms influencing cell survival in the penumbra as well as repair processes following stroke.  One the major mechanisms by which cells respond to hypoxia is by induction of the HIF transcription factors.  The role of HIFs in the brain during stroke and hypoxia is only beginning to be delineated.  By inducing targets involved in angiogenesis (VEGF), neuroprotection (EPO) or glycolysis, some reports suggest an adaptive role of HIFs during hypoxia and ischemia.  Yet, HIFs also induce the expression of pro-apoptotic members of the Bcl-2 family and thus likely mediate a pathological role under some conditions.  We have recent evidence that HIF function within astrocytes regulates specific hypoxia-induced cross-talk between astrocytes and neurons that alter neuronal viability.  To explore these interests, we utilize transgenic mice with conditional loss of HIF-1 function.  Employing co-cultures of astrocytes and neurons with selective loss of HIF-1 within neurons or astrocytes we can determine the impact of HIF-1 function within each cell type.  Moreover, we also examine selective loss of HIF-1 function within select cell types in the brain during hypoxia and ischemia.  Using this approach, we will extend our in vitro observations to examine cell-type specific effects of HIF-1 in the brain under multiple disease processes that involve hypoxia mediated molecular processes.

A second line of investigation that we pursue involves examining the impact of hypoxia on mitochondrial function.  Mitochondria play a critical role in cell survival during ischemia as they are involved in processes such as ATP production, calcium sequestration, ROS generation, and apoptosis.  We recently identified a novel protein that is induced by hypoxia and localizes to the mitochondria.  We are currently examining the putative role of this protein on the multiple mitochondrial functions that are so critical for tissue survival during hypoxia and ischemia.