Rajiv Ratan, M.D., Ph.D
Director, Burke/Cornell Medical Research Institute
Burke Professor of Neurology, Neuroscience and Rehab Medicine, Weill Medical College of Cornell University                                             
                Biography
           Laboratory Focus
                                          Publications

My laboratory has been interested in understanding how pathological stimuli, particularly oxidative stress, can inappropriately activate programs of cell death in neurons. In pursuing this global question we have set up several in vitro models of oxidative stress-induced death as well as hypoxic-ischemic death. We have used these models to address three major areas of investigation:

1) What are the critical molecular targets for free radicals in neurons in inducing necrotic or apoptotic death?

2) What are the endogenous transcriptional mechanisms that are activated in response to ischemia or oxidative stress and how can these transcriptional programs be pharmacologically engaged to treat neurodegenerative conditions?

3) What are the roles of free radicals and the antioxidant enzymes that regulate them in normal cell function? Indeed, over the past decade we have come to appreciate the roles of hydrogen peroxide and nitric oxide as messengers in the nervous system. Our investigations into these areas over the past decade have established several projects in the lab. In our studies we extend our in vitro findings to animals. These are:

A.) The role of the transcriptional activators, hypoxia-inducible factor-1 (HIF-1) and cAMP response element binding protein (CREB) in regulating survival and death in neurons.

B.) The role of HIF-1 prolyl hydroxylases in cell survival. HIF-1 is a basic-helix-loop-helix transcriptional activator composed of a 120 kDa HIF-1a subunit and a 90-94 kDa HIF-1b subunit. Under normoxic conditions HIF-1a is post translationally ubiquitinated by the E3 ubiquitin ligase, Von Hippel Lindau Protein. Ubiquitination of HIF-1a targets the protein for degradation by the proteasome. Under the appropriate conditions (e.g. hypoxia, or treatment with an antioxidant iron chelator), HIF-1a is stabilized where it can dimerize with HIF-1b and translocate to the nucleus to regulate a cassette of neuroprotective genes including vascular endothelial growth factor, erythropoietin and glycolytic enzymes. The lab has been investigating the mechanisms for the stabilization of HIF-1 in neurons and whether this transcriptional activator is necessary or sufficient for survival in response to hypoxic or oxidative stress in the nervous system. In pursuing our studies of HIF-1, we made the unexpected observation that CREB binding to the hypoxia response element can be enhanced in response to pharmacological and physiological activators of HIF-1. Accordingly, we are examining the role of CREB in stress resistance as well.