Stroke is the third most common cause of death, and the leading cause of chronic neurological disability in the United States, causing substantial health-care expenditures. More than 100 potential therapies for stroke targeting neuronal survival have failed in clinical trials. Development of potential therapies effective after the iniial ischemic event and preferably targeting multiple mechanisms is urgently needed. Experimental ischemia triggers increased neurogenesis in the subventricular and dentate gyrus germinal zones. These endogenous neural precursor cells then migrate to areas of damage. However, the survival of these cells is low, in part due to the surrounding pro-inflammatory milieu. Loss of immature neurons and inflammation are recently recognized roadblocks to recovery. Strategies to improve survival of newly generated neurons and modulate the post-ischemic inflammatory response are thus promising approaches to improve stroke outcome. Mitochondria are primary targets of ischemic injury. Previous work demonstrated that immature Doublecortin+ neurons are particularly vulnerable to mitochondrial impairment, and that protection of mitochondrial function can rescue neurogenesis both in vitro and in vivo. Recent evidence also suggests that mitochondrial function is a key determinant of pro-inflammatory macrophage/microglial activation. Genetic and pharmacological approaches to mitochondrial protection will be used in this proposal to increase understanding of the role of mitochondria in injury response and endogenous repair. The extreme sensitivity of immature neurons to even mild mitochondrial impairment will be addressed in Aim 1 by selectively targeting mitochondrial protection to immature Doublecortin expressing neurons. The effect of mitochondrial protection on neuronal survival of ischemic injury or inflammation will be assessed in vitro. Differentiation and long ter survival of neurons, and neurobehavioral outcome will be assessed in a mouse stroke model.
Aim 2 investigates selectively targeting mitochondrial protection to microglia and evaluates the effect on the microglial inflammatory response and on neurogenesis. Both the differentiation fate and survival of neural precursors are regulated by surrounding glial cells, and pro-inflammatory activated microglia strongly inhibit neurogenesis. Since microglial activation is modulated by mitochondrial function the impact of altered microglial activation on differentiation and survival f new neurons in vitro and after stroke in vivo will be evaluated.
Aim 3 investigates potential mitochondrial protective strategies that can be administered after ischemia. The effect of post-injury mitochondrial targeted protection on neurogenesis, long-term neuronal survival and functional outcome will be assessed. Protecting mitochondria is likely to improve new neuron survival directly and modifying microglial response to ischemia will likely result in enhanced tissue sparing, increased neurogenesis and improved long term neurobehavioral outcome. The role of mitochondria in post-ischemic recovery is a new area with significant potential to identify novel approaches to enhance stroke recovery.

Public Health Relevance

Stroke is the third most common cause of death in the United States, with nationwide stroke-related costs totaling nearly $74 billion in 2010. The long-term goal of this study is to improve recovery following stroke by investigating factors including the generation of new brain cells that are central to brain recovery. This research objective is highly relevant to the NIH's mission of reducing the burden of disease by improving outcome following stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Bosetti, Francesca
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Stanford University
Schools of Medicine
United States
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Stary, Creed M; Giffard, Rona G (2015) Advances in astrocyte-targeted approaches for stroke therapy: an emerging role for mitochondria and microRNAS. Neurochem Res 40:301-7
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