Role of protein acetylation in Huntington's disease

亨廷顿氏病（HD）和其他扩展的多聚谷氨酰胺疾病是晚期- 突变体中谷氨酰胺重复序列扩增引起的神经变性疾病 蛋白目前，对这些痛苦和致命的疾病没有治愈或有效的治疗方法。 扩展的谷氨酰胺重复序列的致病靶点尚不清楚。我们发现 亨廷顿蛋白的多聚谷氨酰胺结构域（Htt）结合并抑制几种 乙酰转移酶（例如CBP，p300和P/CAF），并降低细胞中乙酰化组蛋白的水平 文化 我们已经开发并使用了两种果蝇HD模型来测试以下可能性： 神经病理学可能由乙酰化和转录水平降低引起。我们发现 通过两种独立的机制抑制脱乙酰化过程。遗传上或 HDAC抑制剂可降低致死率并抑制感光神经元 退化这些结果强烈暗示了乙酰化状态的致病过程。 由于包括SAHA在内的几种HDAC抑制剂目前已被FDA批准用于其他临床治疗， 在第一阶段的临床试验中，HDAC抑制剂现在可以被认真考虑， HD和相关疾病的潜在治疗剂。这是早期的案例之一 其中在果蝇模型中鉴定了潜在有用的药理学试剂， 疾病 在这里，我们建议使用果蝇模型来扩展这些研究。在这两种苍蝇和 人类有HAT（组蛋白乙酰转移酶）和HDAC（组蛋白去乙酰化酶）家族 基因（~ 11个HAT和~9个HDAC相关基因）。在这个项目中，我们将确定是否所有或 这些基因中只有一部分与多聚谷氨酰胺的发病机制有关，我们将确定 贡献是否是累加的。这些数据将提高我们对遗传学的理解， 发病机制的分子基础，他们将确定新的治疗靶点，他们将 揭示针对HAT/HDAC循环中多种酶的联合治疗是否可能 要有效率。 公司名称（英文） 地址：University of加州Irvine，Irvine，CA 92697 关键人员请参见instruc_ons。根据需要使用conl/nua_/onpages以如下所示的格式提供所需的信息。 从首席调查员开始。按字母顺序列出所有其他关键人员，姓在前。 名称组织机构项目 J.劳伦斯·马什博士.&细胞生物学，UC Irvine PI 莱斯利·M汤普森博士精神病学和行为学，UC Irvine Co-PI Namita Agrawal博士.&细胞生物学，加州大学欧文分校研究生研究员 Tamas Lukacsovich博士.&细胞生物学，UC Irvine专业研究员50% 马丁·希克斯细胞生物学，加州大学欧文分校研究生 拉兹洛·波代（Lazlo Bodai）细胞生物学，UC Irvine初级专家67% Judit Pallos，细胞生物学，UC Irvine初级专家67% 在报表上披露Perm/ss/。仅适用于BIPJSTTR。参见说明。[]是[]否 ，PHS 398（Rev. 05/01）Page_2 Form Page 2 + 使用_英寸边距。在整个应用程序中，在页面的底部进行编号。不要使用后缀，如3a，3b。 研究者/PDroigract（最大，第一，中间）：马什。J. Lawrence 主要研究者/项目负责人的姓名必须在打印页和续页的顶部提供。 字体密度和尺寸必须符合PHS 398说明中提供的限制和规格。 研究资助 目录 页码 首页.... 1 说明，

Huntington's disease (HD) and other expanded polyglutamine diseases are late- onset neurodegenerative diseases caused by expansion of a glutamine repeat in the mutant protein. Currently, no cure or effective treatment for these agonizing and lethal diseases exists. The pathogenic target of the expanded glutamine repeat is unknown. We find that the polyglutamine domain of Huntingtin (Htt) binds to and inhibits the activity of several acetyltransferases (e.g.CBP, p300, and P/CAF) and reduces the level of acetylated histones in cell culture. We have developed and used two Drosophila models of HD to test the possibility that neuropathology may result from reduced levels of acetylation and transcription. We find that inhibition of the deacetylation process by two independent mechanisms Le. genetically or pharmacologically (HDAC inhibitors) reduces lethality and arrests photoreceptor neuron degeneration. These results strongly implicate the state of acetylation in the pathogenic process. As several HDAC inhibitors, including SAHA, are currently FDA approved for use in other clinical settings or are in Phase I clinical trials, HDAC inhibitors can now be seriously considered as potential therapeutic agents for HD and related diseases. This represents one of the early cases where potentially useful pharmacologic agents have been identified in a Drosophila model of disease. Here we propose to extend these studies using the Drosophila model. In both flies and man there are families of HAT (Histone Acetyl Transferase) and HDAC (Histone DeACetylase) genes (-11 HATs and ~9 HDAC related genes). In this project, we will determine whether all or just some of these genes are relevant to polyglutamine pathogenesis and we will determine whether contributions are additive. These data will improve our understanding of the genetic and molecular basis of pathogenesis, they will identify new targets for therapeutics and they will reveal whether combination therapies targeted at multiple enzymes in the HAT/HDAC cycle might be effective. PERFORMANCSEITE(S)(organizatiocnit,ys, tate) University of California, Irvine, Irvine, CA 92697 KEY PERSONNEL See instruc_ons. Use conl/nua_/onpages as neededto providethe requiredinformationinthe format shown below. Startwith PrincipalInvestigator. List all other key personnel in alphabetical order, last name first. Name Organization Roleon Project J. Lawrence Marsh, Ph.D. Devel.& Cell Biology, UC Irvine PI Leslie M. Thompson Ph.D. Psychiatry and Hum Behavior, UC Irvine Co-PI Namita Agrawal Ph.D. Devel.& Cell Biology, UC Irvine Post graduate researcher Tamas Lukacsovich Ph.D. Devel.& Cell Biology, UC Irvine Professional researcher 50% Martin Hicks Devel.& Cell Biology, UC Irvine graduate student Lazlo Bodai Devel.& Cell Biology, UC Irvine Junior specialist 67% Judit Pallos Devel.& Cell Biology, UC Irvine Junior specialist 67% Disclosure Perm/ss/on Statement. Applicable tO$BIPJSTTR Only. See instructions. [] Yes [] No , PHS 398 (Rev. 05/01) Page_2 Form Page 2 + Use_-inch MARGINS. Number pages consecutivelyat the bottomthroughoutthe application.Do not use suffixessuchas 3a, 3b. PdndpInavl estigator/PDroigreract(mLoarst, first,middle): Marsh. J. Lawrence The name of the principalinvestigator/programdirectormust be providedat the top of each printedpage and each continuationpage. Type density and size must conform to limits and specifications provided in the PHS 398 Instructions. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ..................................................................................................................................... 1 Description,