Our proposal is based upon new and important findings involving changes in mitochondrial structure and function in cerebral arteries after ischemia which are of scientific interest because they overturn accepted thinking concerning mitochondrial status and function after ischemia. These findings are of translational interest because they open up novel therapeutic avenues which can be used in people following strokes. Our overall hypothesis, derived from our discoveries, is that naturally occurring and drug inducible changes in mitochondria, primarily in endothelium following ischemia, lead to improved cerebral vascular function, preserved blood-brain barrier, and reduced neurological injury. We find that mitochondria are more resiliant after ischemic insult than previously believed and thus represent a novel therapy in stroke patients. The stroke model we use induces patterns of cerebral vascular and brain injury similar to those seen in patients in which the vascular occlusion is not removed until 3 or more hours following the onset of stroke. Several studies have shown that tPA administration in a 3- to 4.5-hour window after stroke onset shows a modest therapeutic benefit with little benefit beyond 4.5 hours. These patients in the 3-4.5 hour post-onset period represent a large and extremely vulnerable population. We expect that mitochondrial targeting in addition to clot removal will lessen morbidity and mortality in these patients. We will test our hypothesis in cultured cerebral vascular endothelial cells, isolated cerebral arteries, and the in vivo cerebral circulation.
Aim 1. Determination of naturally occurring morphological and functional changes in mitochondria in the cerebral vasculature following ischemic stress. We will test the hypothesis that structural changes in mitochondria, including size, numbers, and/or protein content, especially in endothelium, are correlated with functional changes involving maintained dilator and protective responses following ischemia.
Aim 2. Determination of inducible changes in mitochondrial dynamics in the cerebral vasculature following ischemic stress. We will test the hypothesis that pharmacologically-induced post-conditioning will further improve upon natural mitochondrial-dependent processes in the cerebral circulation following ischemia.

Public Health Relevance

Current therapies for people with occlusive strokes are limited even after resolution of the clot especially beyond the 3 hour window following the onset of stroke. We believe that exploitation of mitochondrial mechanisms, as we propose, could benefit the brain by protecting cerebral vascular cells from further injury, correcting cerebral hypoperfusion, protecting the blood-brain barrier, and restoring normal cerebral vascular responsiveness.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL093554-08
Application #
9197668
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Charette, Marc F
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Tulane University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Rutkai, Ibolya; Dutta, Somhrita; Katakam, Prasad V et al. (2015) Dynamics of enhanced mitochondrial respiration in female compared with male rat cerebral arteries. Am J Physiol Heart Circ Physiol 309:H1490-500
Dutta, Somhrita; Rutkai, Ibolya; Katakam, Prasad V G et al. (2015) The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. J Neurochem 134:845-56
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-β toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9
Wappler, Edina A; Institoris, Adam; Dutta, Somhrita et al. (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PLoS One 8:e63206
Nautiyal, Manisha; Katakam, Prasad V G; Busija, David W et al. (2012) Differences in oxidative stress status and expression of MKP-1 in dorsal medulla of transgenic rats with altered brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 303:R799-806

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