Identification of Novel Drugs against Huntington's Disease and Cerebral Ischemia

描述（由申请人提供）：本提案的主要研究者王欣博士是布里格姆妇女医院和哈佛医学院的神经外科讲师。该提案概述了王博士的研究从筛选亨廷顿病的新药（她目前的导师项目）到寻找减少缺血性中风影响的化合物的指导过渡。后一项调查将是她独立学术活动的主题。从那时起，她将申请R01级别的资助。该提案的主要导师Robert Friedlander博士目前是一位独立的临床科学家和公认的领导者，在神经疾病的新药物测试和治疗领域拥有丰富的出版经验。联合导师Bruce Kristal博士是线粒体功能障碍和线粒体通透性转变方面的专家，因为它们与程序性细胞死亡有关。共同导师，Michael Moskowitz博士是脑缺血不同模型领域的世界知名专家。一个由博士组成的导师委员会。弗里德兰德、克里斯托和莫斯科维茨以及其他五位科学家（dr . Friedlander, Kristal, Moskowitz）。Connolly, Stein, Glicksman， Li和Cudkowicz)将作为王博士的咨询委员会，并将仔细监督王博士的进展。拟议工作的开展环境（哈佛医学院）是进行基础和临床研究的世界级科研机构。在本项目中，王博士将在培养的两种神经元系统中筛选21种细胞色素c释放抑制剂和11种线粒体通透性转化（mPT）抑制剂。她将从这些候选药物中选择八种最有效的神经保护药物在两种人类疾病小鼠模型中进行测试：R6/2转基因菌株，其综合征类似于亨廷顿氏病（HD）和C57BL/6中大脑中动脉闭塞（MCAO）模型中风。此外，王博士将评估新发现的候选药物发挥其有益作用的分子机制。正如在初步结果部分所述，王博士已经证明了甲基唑胺和褪黑激素成功地抑制了细胞色素c的释放，从而阻断了神经元细胞的死亡。这种分子效应与这些药物在脑卒中小鼠模型中减小梗死面积和减少神经损伤的能力有关。她还提供了去甲替林和异丙嗪的神经保护作用的数据，这些化合物可以抑制mPT。这些在培养细胞和小鼠中进行的实验的最终目标是为HD和中风患者的临床试验提供参数。由于所有被测试的化合物都在目前的临床应用中（用于治疗其他综合征！），它们在最终的人体试验中应该是安全的。

DESCRIPTION (provided by applicant): The principal investigator for this proposal, Dr. Xin Wang, is an Instructor of Neurosurgery at Brigham and Women's Hospital and Harvard Medical School. This proposal outlines a mentored transition of Dr. Wang research from screening novel drugs for Huntington's diseases (her current advisor's project) to searching for compounds that decrease the impact of ischemic stroke. The latter investigation will be the subject of her independent academic activity. From then on she will apply for R01 level funding. The primary mentor for this proposal, Dr. Robert Friedlander, is currently an independent clinical scientist and recognized leader with extensive published experience in the area of novel drug testing and therapy for neurological diseases. The co-mentor, Dr. Bruce Kristal, is an expert in mitochondrial dysfunction and the mitochondrial permeability transition as they relate to programmed cell death. The co-mentor, Dr. Michael Moskowitz is a world-renown expert in the area of different models of cerebral ischemia. A mentor committee consisting of Drs. Friedlander, Kristal and Moskowitz and five other scientists (Drs. Connolly, Stein, Glicksman, Li and Cudkowicz) will serve as the advisory committee for Dr. Wang and will carefully supervise Dr. Wang' progress. The environment in which the proposed work will be carried out (Harvard Medical School) is a world class scientific institution where both basic and clinical researches are conducted. In this project, Dr. Wang will screen the twenty-one inhibitors of cytochrome c release and eleven inhibitors of the mitochondrial permeability transition (mPT) in two systems of cultured neurons. She will select the eight most potently neuroprotective of these candidate drugs for testing in two mouse models of human disease: the R6/2 transgenic strain whose syndrome resembles Huntington's disease (HD) and middle cerebral artery occlusion (MCAO) in C57BL/6 that models stroke. Furthermore, Dr. Wang will evaluate the molecular mechanisms by which the newly identified candidate drugs exert their beneficial effects. As presented in the Preliminarily Result section, Dr. Wang has demonstrated that methazolamide and melatonin successfully inhibit cytochrome c release, thereby blocking neuronal cell death. This molecular effect correlates with these drugs' ability to decrease infarct size and reduced neurological impairment in the mouse model of stroke. She also presents data on the neuroprotective effects of nortriptyline and promethazine, compounds that inhibit mPT. The ulimate goal of these experiments in cultured cells and in mice is to suggest the parameters for clinical trials on patients who suffer HD and stroke. As all the compounds being tested are in current clinical use (to treat other syndromes!), they should be safe for eventual human trials.