Small Molecule Neurotrophin Mimetics to Treat Huntington's Disease

描述（由申请人提供）：该申请题为“小分子神经营养因子模拟物治疗亨廷顿病”，是对NINDS转化研究探索性/发展项目（R21；项目公告：PAR- 08-232）的回应。目前的提案将测试TrkB神经营养因子受体的小分子激动剂是否能有效治疗亨廷顿病（HD）相关的神经变性。TrkB受体结合脑源性神经营养因子（BDNF）， BDNF是一种生长因子，在神经元存活和突触功能中起关键作用。BDNF水平的降低对许多神经退行性疾病（包括阿尔茨海默病、帕金森病和亨廷顿舞蹈症）的病理有重要影响。鉴于BDNF/TrkB广泛的神经保护作用，对缺乏不良副作用的小分子TrkB配体的需求是巨大且长期存在的。这类化合物是申请人及其同事首次开发的。在体外和体内研究中，这些新型TrkB激动剂模拟了BDNF对TrkB信号传导和细胞存活的许多影响。因此，它们在预防神经退行性疾病病理方面的作用已经准备好进行测试。该提案将重点关注HD，因为HD大脑中BDNF的丢失是与该疾病相关的神经病理的基本因素。HD是一种致命的神经退行性疾病，其特征是在成年期出现进行性运动、心理和认知缺陷。它是由编码亨廷顿蛋白的基因突变引起的。拟议的研究将使用HD转基因小鼠模型来实现两个目标：(i)通过一系列行为测试确定两种不同的BDNF模拟物是否会减缓或预防与HD相关的运动、记忆和精神缺陷的出现；（ii）测试BDNF模拟物是否能改善hd相关的神经病理学。这些研究的积极结果将确定一种新的可行的治疗策略，用于减少许多HD表型（运动，心理和认知障碍以及神经病理学），这些表型目前无法治疗，以及其他与年龄相关的神经退行性疾病。目前的R21提案旨在提供概念验证和靶标验证数据，以支持随后的U01应用，以确定这些新型小分子TrkB配体对抗神经变性的有效性。

DESCRIPTION (provided by applicant): This application titled "Small Molecule Neurotrophin Mimetics to Treat Huntington's Disease" is in response to NINDS Exploratory/Developmental Projects in Translational Research (R21; program announcement: PAR- 08-232). The current proposal will test whether small molecule agonists for the TrkB neurotrophin receptor will be effective treatments for neurodegeneration associated with Huntington's Disease (HD). The TrkB receptor binds brain derived neurotrophic factor (BDNF), which is a growth factor that is critically involved in neuronal survival and synapse function. Reduced levels of BDNF contribute importantly to pathology in numerous neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's (HD). Given the pervasive neuroprotective role of BDNF/TrkB, the demand for small molecule TrkB ligands that lack undesired side- effects is large and long standing. Such compounds have been developed for the first time by the applicant and his colleague. These novel TrkB agonists mimic many of BDNF's effects on TrkB signaling and cell survival in in vitro and in vivo studies. Thus, they are ready to be tested for their effects on preventing pathology in neurodegenerative disease. This proposal will focus on HD since the loss of BDNF in HD brains is a fundamental contributor to the neuropathologies associated with the disorder. HD is a fatal neurodegenerative disease characterized by progressive motor, psychological, and cognitive deficits that emerge in adulthood. It is caused by a mutation in the gene that encodes the huntingtin protein. The proposed studies will use a transgenic mouse model of HD to execute two aims: (i) determine if 2 different BDNF mimetics will slow the emergence of, or prevent, motor, memory and psychiatric deficits associated with HD using a battery of behavioral tests; and (ii) test whether BDNF mimetics ameliorate HD-related neuropathology. Positive results in these studies will identify a novel and feasible therapeutic strategy for reducing numerous HD phenotypes (motor, psychological and cognitive impairments as well as neuropathology), which are currently untreatable, as well as other age-related neurodegenerative diseases. The current R21 proposal is designed to provide proof-of-concept and target validation data that will support a subsequent U01 application to determine the effectiveness of these novel small molecule TrkB ligands against neurodegeneration. PUBLIC HEALTH RELEVANCE: The current proposal will test the efficacy of novel, small molecule agonists for the TrkB neurotrophin receptor to treat neurodegenerative disease, specifically Huntington's Disease (HD). The TrkB receptor binds brain derived neurotrophic factor (BDNF), the loss of which in HD brains is a fundamental contributor to the neuropathologies associated with the disorder. Thus, these first-in-class TrkB agonists are likely candidates to prevent neurodegeneration associated with a disease that currently has no cure and success in the proposed HD studies will point to TrkB agonist applications in other CNS disorders including Alzheimer's disease and depression.