La Spada Outstanding Investigator Award

拉斯帕达杰出研究者奖

基本信息

批准号：
10227293
负责人：
ALBERT R LA SPADA
金额：
$ 99.54万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2029-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10227293
关键词：
AR gene Aging Agonist Androgen Receptor Area Award Bacterial Artificial Chromosomes CAG repeat Cerebral cortex Communication Corpus striatum structure Development Disease Excision Functional disorder Funding Gene Expression Genetic Transcription Grant Homeostasis Huntington Disease Huntington gene Huntington protein Inherited Investigation Link Lower Motor Neuron Disease Metabolic Microglia Molecular Motor Neuron Disease Motor Neurons Mus Muscular Atrophy National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Neurons PPAR delta Paper Pathogenesis Pathway interactions Patients Phenotype Play Process Publishing Regulation Repression Research Research Personnel Role Series Skeletal Muscle Testing Time Transcription Coactivator Transgenes Transgenic Mice Translational Research Type 7 Spinocerebellar Ataxia Work career disease phenotype flexibility follow-up functional decline graduate student mitochondrial dysfunction motor neuron degeneration mouse model mutant nervous system disorder neuroinflammation neuromuscular neuroprotection neurotoxicity novel novel therapeutics polyglutamine prevent programs research and development response skeletal muscle wasting spinal and bulbar muscular atrophy stem cell model stem cells therapy development transcriptome

项目摘要

Abstract I have been studying neurodegenerative disease for more than 30 years. While a graduate student, I identified the cause of X-linked spinal and bulbar muscular atrophy (SBMA) as the expansion of a CAG repeat in the androgen receptor (AR) gene. As the first disorder shown to be caused by a CAG – polyglutamine (polyQ) repeat tract, this discovery led to the emergence of a new field. My research program began with emphasis on 2 polyQ disorders: SBMA and spinocerebellar ataxia type 7 (SCA7). My early work established transcription dysregulation as a key factor in polyQ disease pathogenesis. I initiated research on Huntington’s disease (HD), and linked mitochondrial dysfunction and metabolic deficits in HD to transcription dysregulation of PGC-1a, a transcription co-activator. In 2016, I documented an interaction between PPARd and huntingtin (htt) protein in striatal-like neurons and in the cerebral cortex of HD mice, and I demonstrated that PPARd repression contributes to HD neurotoxicity. These findings led me to repurpose a selective and potent PPARd agonist, KD3010, as capable of rescuing htt neurotoxicity in HD transgenic mice and in medium spiny neurons from HD patient stem cells. Concomitant with my HD research, I uncovered a central role for skeletal muscle in SBMA by demonstrating that excision of mutant AR transgene from skeletal muscle in BAC conditional transgenic mice prevented the development of neuromuscular SBMA phenotypes, establishing the importance of skeletal muscle – motor neuron (MN) communication at the neuromuscular junction (NMJ) for SBMA lower MN disease. I have thus continuously maintained NINDS R01 funding to support my SBMA research since 2000, and have held NINDS R01 funding to support my HD research since 2010. During this time frame, my research has increasingly focused on identification of targets and pathways for development of therapies. As a R35 recipient, I will continue my research on the cellular and molecular basis of polyQ neurodegeneration, embracing opportunities to extend our findings to more common neurodegenerative diseases, including AD, PD, and ALS. One major focus will be to define the basis of SBMA muscle-driven MN disease through skeletal muscle and NMJ transcriptome analysis of SBMA model mice and stem cell modeling to recapitulate non-cell autonomous SBMA MN degeneration. I also intend to pursue studies of HD and PPARd by determining the normal function of PPARd in CNS and defining how PPARd activation achieves neuroprotection. I will follow up on exciting findings linking PPARd neuroprotection to regulation of neuronal activity-dependent gene expression, and will test if blunting of rapid primary response gene expression can ameliorate HD phenotypes. As PPARd is highly expressed in microglia and represses neuroinflammation, I will study PPARd function in microglia and test if PPARd dysregulation plays a role in neurodegenerative disease. R35 funding would provide me with the flexibility to pursue novel, ambitious studies of polyQ disease, expand my research program to encompass emerging areas of pathogenesis, and maintain a lasting commitment to translational research and therapy development for neurodegeneration.

抽象的当我还是一名研究生时，我发现神经退行性疾病已经研究了 30 多年。 X连锁脊髓和延髓肌萎缩症（SBMA）的原因是CAG重复序列的扩展雄激素受体 (AR) 基因是第一个被证明由 CAG 引起的疾病 - 聚谷氨酰胺。（polyQ）重复序列，这一发现导致了一个新领域的出现，我的研究计划由此开始。重点关注 2 种 PolyQ 疾病：SBMA 和脊髓小脑性共济失调 7 型 (SCA7)。转录失调是 PolyQ 疾病发病机制的关键因素我发起了对亨廷顿舞蹈症的研究。疾病（HD），并将 HD 中的线粒体功能障碍和代谢缺陷与转录失调联系起来 2016 年，我记录了 PPARd 和亨廷顿蛋白之间的相互作用。 (htt) 蛋白存在于 HD 小鼠的纹状体样神经元和大脑皮层中，我证明了 PPARd 抑制会导致 HD 神经毒性。这些发现促使我重新利用选择性且有效的 PPARd。激动剂 KD3010，能够挽救 HD 转基因小鼠和中型多棘神经元的 htt 神经毒性伴随我的 HD 研究，我发现了骨骼肌的核心作用。在 SBMA 中，通过证明在 BAC 条件下从骨骼肌中切除突变 AR 转基因转基因小鼠阻止了神经肌肉 SBMA 表型的发展，确立了其重要性骨骼肌 - 运动神经元 (MN) 在神经肌肉接头 (NMJ) 处的通讯对于 SBMA 的影响较低因此，从那时起我就一直维持 NINDS R01 资金来支持我的 SBMA 研究。 2000 年，并自 2010 年以来一直持有 NINDS R01 资金来支持我的 HD 研究。在此期间，我的研究越来越侧重于确定治疗方法的靶点和途径。 R35 接受者，我将继续研究 PolyQ 神经变性的细胞和分子基础，抓住机会将我们的发现扩展到更常见的神经退行性疾病，包括 AD， PD 和 ALS 的主要焦点是通过骨骼来定义 SBMA 肌肉驱动的 MN 疾病的基础。 SBMA 模型小鼠的肌肉和 NMJ 转录组分析以及干细胞建模以概括非细胞我还打算通过确定 SBMA MN 变性来研究 HD 和 PPARd。我将了解 PPARd 在 CNS 中的正常功能，并定义 PPARd 激活如何实现神经保护。令人兴奋的发现将 PPARd 神经保护与神经元活动依赖性基因的调节联系起来表达，并将测试快速初级反应基因表达的减弱是否可以改善 HD 表型。由于 PPARd 在小胶质细胞中高表达并抑制神经炎症，因此我将研究 PPARd 在小胶质细胞中的功能小胶质细胞并测试 PPARd 失调是否在神经退行性疾病中发挥作用。为我提供灵活性，以追求 PolyQ 疾病的新颖、雄心勃勃的研究，扩大我的研究范围计划涵盖发病机制的新兴领域，并保持对转化的持久承诺神经退行性疾病的研究和治疗开发。