Neurorestorative Therapy for Stroke Injury

中风损伤的神经恢复治疗

• 批准号: 9795370
• 负责人: Inderjit Singh
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795370
• 关键词: Acute; Adult; Adverse effects; Age; Aging; American; Animal Model; Animals; Brain; Calcium; Calpain; Cardiovascular Diseases; Cell Culture Techniques; Cell Death; Cells; Cerebrum; Chronic Phase; Clinical; Clinical Trials; Development; Disease; Drug Targeting; Economic Burden; Elderly; Experimental Animal Model; Experimental Designs; Glutathione Disulfide; Homeostasis; Human; Impairment; In Vitro; Injury; Ischemia; Ischemic Stroke; Journals; Laboratories; Maintenance; Mediating; Modeling; Morbidity - disease rate; Mus; Nerve Degeneration; Neurology; Neurons; Neurosciences; Nitric Oxide; Nitric Oxide Synthase Type I; Outcome; Pathologic; Pathology; Peptide Hydrolases; Peroxonitrite; Pharmaceutical Preparations; Physiological; Play; Press Releases; Production; Property; Reaction; Recovery; Recovery of Function; Regulation; Rehabilitation therapy; Reperfusion Therapy; Reporting; Risk Factors; Role; S-Nitrosoglutathione; Stroke; Subarachnoid Hemorrhage; Superoxides; System; Testing; Toxic effect; Vascular Diseases; Veterans; aged; aging brain; aging population; base; clinically relevant; design; disability; editorial; effective therapy; excitotoxicity; improved; induced pluripotent stem cell; inhibitor/antagonist; mature animal; metabolome; mouse model; nervous system disorder; neurobehavioral; neurorestoration; neurovascular; novel; novel strategies; pre-clinical; rehabilitation strategy; stroke model; stroke patient; stroke recovery; stroke risk; stroke survivor; stroke therapy; tool; young adult

Aging is the major non-modifiable stroke risk factor in humans, and ischemic stroke is highly prevalent in aged Veterans and other Americans, with an economic burden exceeding $70 billion/year. Furthermore, the rate and the degree of functional recovery in aged stroke patients, as in aged animal models of stroke, are slower than in the young. In the aged brain, excitotoxicity-induced sustained neuronal peroxynitrite production is more prominent, causing sustained calpain activation and thus neurodegeneration. We observed that this deleterious activity of peroxynitrite can be blocked by S-nitrosoglutathione (GSNO), a reaction product of NO and glutathione. GSNO inhibits neuronal nitric oxide synthase (nNOS)-derived peroxynitrite formation in mouse models of stroke. Therefore, using aged mouse models, we propose to investigate the critical roles of peroxynitrite versus GSNO in functional recovery from stroke. Mechanistic stroke studies using animal-derived cell culture models have not been validated in humans, frustrating the development of mechanism-based neuroprotective human stroke therapy. Therefore, we propose using induced pluripotent stem cell (iPSC)-derived human neurons to investigate the effect of peroxynitrite versus GSNO-mediated mechanisms in excitotoxicity-induced toxicity under stroke conditions. Studies on the regulation of nNOS/calpain system indicate that a complete irreversible inhibition using specific inhibitors of nNOS/calpain limits not only the cellular insult but also vital physiologic functions. In contrast, the proposed GSNO-mediated reversible inhibition of nNOS and calpain offers a novel approach which we hypothesize will be effective by maintaining physiologic function and inhibiting pathological activities. We hypothesize that deleterious activities of the nNOS/peroxynitrite/calpain system are maintained more persistently in the aged than the young stroke brain. High levels of peroxynitrite and up regulated activity of calpains cause profound neurodegeneration, whereas, GSNO, via the mechanism of S- nitrosylation, reversibly inhibits the activities of nNOS and calpain to reduce peroxynitrite-induced neurodegeneration and accelerate functional recovery in aged stroke mice. The hypothesis will be tested via two specific aims. Specific aim 1 elucidates the regulatory mechanisms through which GSNO inhibits the deleterious nNOS/peroxynitrite/calpain system under stroke conditions in iPSC-derived human neuronal culture model. Specific Aim 2 investigates whether GSNO aids and accelerates functional recovery by blocking the deleterious nNOS/peroxynitrite/calpain system in aged mouse stroke models. Expected outcomes include elucidation of GSNO-mediated mechanisms for inhibition of the nNOS/peroxynitrite/calpain system and functional recovery in aged animals. iPSC-derived human neurons will provide a new tool to understand the mechanisms of human stroke injury, leading to the development of a therapy of translational value for stroke survivors including senior citizens and Veterans. GSNO is a component of the human brain and body, and its efficacy has been documented in several animal models of neurovascular, cardiovascular and vascular diseases.

衰老是人类不可改变的主要卒中危险因素，缺血性卒中在老年人中非常普遍