Histone deacetylases - therapeutic targets for functional restoration after strok

组蛋白脱乙酰酶 - 中风后功能恢复的治疗靶点

• 批准号: 8243635
• 负责人: RICHARD S MORRISON
• 金额: $ 33.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243635
• 关键词: Accounting; Acute; Adult; Affect; Anatomy; Animal Model; Animals; Antigens; Apoptosis; Apoptotic; Aspirin; Autopsy; Biological Preservation; Brain; Brain region; Bromodeoxyuridine; Cause of Death; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cerebral Ischemia; Cessation of life; Clinical Treatment; Clinical Trials; Corpus striatum structure; Cyan Fluorescent Protein; Data; Development; Enzymes; FDA approved; Fiber; Frequencies; Funding Opportunities; Generations; Glucose; Health Resources; Histologic; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Human; In Situ; In Vitro; Individual; Infarction; Injury; Intervention; Ischemia; Ischemic Stroke; Lead; MS-275; Malignant Neoplasms; Mediating; Methods; Middle Cerebral Artery Occlusion; Mitochondria; Mitotic; Modeling; Monitor; Morphology; Motor; Mus; Myelin; Natural regeneration; Nervous System Physiology; Neuronal Differentiation; Neurons; Optic Nerve; Outcome; Outcome Measure; Oxygen; Pathology; Pharmaceutical Preparations; Preparation; Process; Production; Proteins; Recovery; Recovery of Function; Research; Safety; Sensory; Stem cells; Stroke; Subfamily lentivirinae; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Transient Cerebral Ischemia; Vorinostat; brain repair; cellular transduction; cognitive recovery; density; deprivation; design; disability; drugged driving; enzyme activity; excitotoxicity; functional outcomes; functional restoration; gray matter; improved; inhibitor/antagonist; interest; killings; knock-down; meetings; nerve stem cell; neurogenesis; neuron loss; neuronal cell body; neuroprotection; newborn neuron; novel strategies; post stroke; postnatal; progenitor; protective effect; public health relevance; research study; response; restoration; selective expression; small hairpin RNA; therapeutic target; thrombolysis; white matter

DESCRIPTION (provided by applicant): Finding interventions that improve outcome from ischemic stroke has proved to be challenging and current treatment is limited to thrombolysis, aspirin, and management in a stroke unit. An ideal stroke therapeutic would minimize damage to mature neurons and white matter, and also maximize the generation of new neurons from endogenous progenitors. Recent findings of our own and of others, both in vitro and in animal models of stroke, suggest that histone deacetylase (HDAC) inhibitors meet these criteria. Drug administration protects isolated neurons from induced apoptotic cell death and white matter from oxygen-glucose deprivation, results in improved histologic and functional outcomes following cerebral ischemia, and appears to drive 'neuronal' differentiation of multipotent neural progenitor cells. Therefore, we hypothesize that HDAC inhibition in stroke may have acute effects (to ameliorate white matter excitotoxicity), and in the intermediate and longer term, added benefit by reducing apoptosis and encouraging regeneration. As a number of HDAC inhibitors are either already approved by the FDA (vorinostat), or well-advanced in clinical trials (MS-275) for other reasons, then re- purposing one or more of these drugs for stroke could be expedited. In addition, development of new and specific inhibitors is ongoing, especially against the Class I HDACs which are the focus of interest here. Studies described in Aim 1 are designed to identify the specific HDACs which account for the beneficial actions of these inhibitors, using in vitro and ex vivo preparations in which individual HDACs are knocked down with shRNA and transduced cells/tissues then subjected to oxygen-glucose deprivation. Having identified specific HDACs, we shall explore in Aim 2 the potential substrates and mechanisms responsible for the beneficial actions of HDAC inhibition. Finally, in the last aim we consider whether treatment of mice with MS-275, a Class I HDAC inhibitor, preserves anatomic integrity and promotes long term functional (motor, sensory, cognitive) recovery from transient cerebral ischemia (middle cerebral artery occlusion), and whether restoration of function correlates with the extent of 'neuronogenesis'. Two recently developed transgenic lines, p53+/+ and p53 -/- mitoCFP mice, will be employed so that we can monitor ischemic pathology in CFP+ fiber tracts, assess drug-associated changes in mitochondrial frequency and distribution within neuronal cell bodies and their processes, and also determine whether HDAC inhibition ultimately involves targets in addition to neuronal p53. PUBLIC HEALTH RELEVANCE: This proposal is submitted in response to PA-08-099 Mechanisms of functional recovery after stroke, "a funding opportunity to promote research to understand the processes of brain repair that lead to functional recovery in order to develop methods to optimize existing practices and to develop new approaches to improve post-stroke outcomes". Currently, there is no drug available to enhance neuroprotection and restore function following human stroke. Experimental animal studies suggest that broad inhibition of histone deacetylase (HDAC) activities in the brain following injury results in neuronal protection and also promotes the generation of new neurons. The purpose of the studies outlined in this proposal is to identify which HDACs are involved in order to select specific drugs to target these particular enzymes. Selected drugs will be tested to reveal what functional benefits they confer on the recovery of mice from stroke injury.

描述（由申请人提供）：发现从缺血性中风改善结果的干预措施被证明是具有挑战性的，目前的治疗仅限于中风单元中的溶栓，阿司匹林和管理。理想的中风治疗将最大程度地减少对成熟神经元和白质的损害，并最大程度地从内源性祖细胞产生新的神经元。在体外和中风模型中，我们自己和其他人的最新发现表明组蛋白脱乙酰基酶（HDAC）抑制剂符合这些标准。药物给药可保护孤立的神经元免受诱导的凋亡细胞死亡和白质的侵害，从而在脑缺血后改善了基础和功能性结果，并且似乎驱动了多核神经祖细胞的“神经元”分化。因此，我们假设中风中的HDAC抑制作用可能具有急性作用（可以改善白质兴奋性毒性），并且在中级和长期中，可以通过减少凋亡和鼓励再生来增加受益。由于许多HDAC抑制剂已被FDA（Vorinostat）批准，或者出于其他原因在临床试验（MS-275）中进行了良好的研究，因此可以加快将其中一种或多种药物重新加速。此外，正在进行新的和特定的抑制剂的发展，尤其是针对I级HDAC，这是这里感兴趣的重点。 AIM 1中描述的研究旨在鉴定特定的HDAC，这些HDAC使用体外和体内制剂，这些抑制剂的有益作用是用shRNA和转导的细胞/组织，然后受到氧气 - 葡萄糖的剥夺。确定了特定的HDAC后，我们将在AIM 2中探索潜在的底物和机制，负责HDAC抑制的有益作用。最后，在最后一个目标中，我们考虑使用MS-275（I类HDAC抑制剂）的小鼠保留解剖完整性，并促进长期功能（运动，感觉，感觉，认知）从短暂性脑缺血（中大脑中部动脉闭塞）中恢复，以及功能恢复与'Neuronon of neuronepense of neuronepense的功能是否相关。 Two recently developed transgenic lines, p53+/+ and p53 -/- mitoCFP mice, will be employed so that we can monitor ischemic pathology in CFP+ fiber tracts, assess drug-associated changes in mitochondrial frequency and distribution within neuronal cell bodies and their processes, and also determine whether HDAC inhibition ultimately involves targets in addition to neuronal p53. 公共卫生相关性：该提案是针对PA-08-099中风后的功能恢复机制提交的。当前，尚无药物来增强人类中风后神经保护和恢复功能。实验动物研究表明，在损伤后，大脑中组蛋白脱乙酰基酶（HDAC）活性的广泛抑制会导致神经元保护，并促进新神经元的产生。该提案中概述的研究的目的是确定涉及哪些HDAC，以选择特定的药物来靶向这些特定的酶。选定的药物将进行测试，以揭示他们从中风损伤中恢复小鼠的功能益处。