Unraveling Cell Death Mechanisms After Intracerebral Hemorrhage

• Applicant: Professorin Dr. Marietta Zille, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 298966395

Although less common than its ischemic counterpart, intracerebral hemorrhage (ICH, 15-20% of all strokes) has the highest mortality rate among all stroke types (~50% at 30 days). Treatment options for reducing mortality and morbidity for ICH are limited. Despite its growing public health importance, our understanding of how permanent damage to the brain occurs following ICH that fosters mortality and disability is incomplete. Given the limited capacity of the brain to repair spontaneously, an important, immediate strategy for reducing disability is to prevent the loss of neurons and this forms the fundamental basis of the proposal before you.In order to accomplish this important goal, we must understand the underlying mechanisms of how brain cells are lost in response to bleeding in the brain. As neurons have unique cytoarchitectures that involve a cell body (control tower) and an emerging axon (that functions like a telephone line) that can connect neuronal cell bodies with other neurons several feet away, it is important to know whether pathological events in the cell body or the axon, or both, mediate loss of function after ICH.The present proposal seeks to test the specific hypothesis that the mechanisms of neuronal death after intracerebral hemorrhage in the cell body and axons are different, actively regulated, and age-dependent.This grant will leverage what is known about the distinct mechanisms and flavors of how cells die to develop a novel therapeutic approach to reducing injury following ICH. I will use pharmacological drugs in conjunction with highly sophisticated electron microscopy to assess the morphology of cells while they are actively dying and how this can be prevented. Moreover, manipulation of potential therapeutic targets using state-of-the-art molecular biology will ultimately converge on a more complete identification and validation of potential pathways for therapeutic intervention.The rigorous approach I have outlined above is time-tested and I have already identified new targets for intervention. However, as of now, this approach has not delivered to treat human hemorrhagic stroke and I will add two important variables to our studies (not examined before) to enhance the likelihood of translation to the human bedside. First, I hypothesize that mechanisms of cell damage and loss following ICH are largely different in the cell body and its associated axon, which I will investigate using microfluidic chambers. Second, to address the question of whether aging affects the mechanism of cell death in the cell body or axon, I propose to use a genetic strategy involving the forced expression of progerin mutants in brain neurons.By incorporating two new variables not normally included in ICH studies, we anticipate identifying new and more readily translatable therapeutic approaches for ICH. We expect this will create a new approach that could be adapted by others of how to identify and validate targets for ICH stroke therapy.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Rajiv Ratan, Ph.D.