Ischemic stroke remains one of the most prevalent and devastating neurological diseases for which limited treatment options are available. Therefore, new therapeutic approaches are sorely needed. Brain ischemia causes severe and often irreversible mitochondrial damage in the early phase of tissue infarction. In turn, damaged mitochondria further exacerbate brain injury by producing free radicals and promoting cell death. A mechanistic understanding of how mitochondrial function is impaired in the ischemic brain may unveil new approaches to protect mitochondria and lead to the development of new strategies for neuroprotection. We have discovered that the mitochondrial protein prohibitin (PHB) is upregulated by ischemic preconditioning and demonstrated that PHB expression by gene transfer protected cultured cortical neurons from oxygen glucose deprivation and hippocampal CA1 neurons from the delayed degeneration produced by transient forebrain ischemia in vivo. These studies clearly suggested a strong neuroprotective potential of PHB but mechanisms pertaining to the neuroprotection, especially those attributed specifically to mitochondria, need to be elucidated. For this purpose, we have developed conditional PHB transgenic (PHB-Tg) mice that express PHB selectively in neurons or astrocytes. Using these mice we propose to test the hypothesis that PHB, by regulating critical mitochondrial functions, modulates the mitochondria's susceptibility to ischemia and protects the ischemic brain from injury. In particular, we will use a model of focal cerebral ischemia produced by transient occlusion of the middle cerebral artery (MCA) to investigate whether conditional neuronal or astrocytic expression of PHB ameliorates ischemic brain injury. Furthermore, we will examine the bioenergetic mechanisms underlying mitochondrial protection by PHB, and its role in preserving mitochondrial network integrity by regulating mitochondrial fusion and fission and cristae structure in ischemic neurons. The findings of the research from the present proposal, therefore, will advance our understanding of how PHB modulates mitochondrial structure, function and dynamics, and will provide new therapeutic targets for ischemic injury based on modulating PHB expression. The findings will also advance our understanding of the fundamental processes governing neuronal survival and death through regulation of mitochondrial dynamics, and have the potential of identifying mitochondria targeted treatment strategies for other neurological diseases linked to mitochondrial dysfunction.

Public Health Relevance

The proposed studies will investigate a novel aspect of prohibitin (PHB), related to its role in the ischemic neuronal injury and on mitochondrial functions. The findings will advance our understanding of the fundamental processes governing neuronal survival and death through regulation of mitochondrial dynamics, and have the potential of identifying mitochondria targeted treatment strategies for stroke and other neurological diseases linked to mitochondrial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067078-10
Application #
9658561
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bosetti, Francesca
Project Start
2009-09-15
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Kurinami, Hitomi; Shimamura, Munehisa; Ma, Tao et al. (2014) Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction. Stroke 45:1131-8
Zhou, Ping; Qian, Liping; D'Aurelio, Marilena et al. (2012) Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities. J Neurosci 32:583-92
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