La Spada Outstanding Investigator Award

摘要 我研究神经退行性疾病已经30多年了。当我还是一名研究生时， X连锁脊髓和延髓肌萎缩症（SBMA）的原因是CAG重复的扩展， 雄激素受体（AR）基因。作为第一种由CAG -聚谷氨酰胺引起的疾病， （polyQ）重复序列，这一发现导致了一个新领域的出现。我的研究项目始于 强调2种polyQ障碍：SBMA和脊髓小脑共济失调7型（SCA 7）。我早期的工作建立了 转录失调是polyQ疾病发病机制中的关键因素。我开始研究亨廷顿舞蹈症 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 PGC-1a是一种转录辅激活因子。2016年，我记录了PPARd和亨廷顿蛋白之间的相互作用， (htt)在纹状体样神经元和HD小鼠的大脑皮层中，我证明了PPARd 抑制有助于HD神经毒性。这些发现使我重新设计了一种选择性的和有效的PPARd 激动剂，KD 3010，能够挽救HD转基因小鼠和中型多棘神经元中的htt神经毒性 HD患者的干细胞。伴随着我的HD研究，我发现了骨骼肌的核心作用， 在SBMA中，通过证实突变AR转基因在BAC条件下从骨骼肌中切除 转基因小鼠阻止了神经肌肉SBMA表型的发展，确立了 神经肌肉接头（NMJ）处骨骼肌-运动神经元（MN）通讯的SBMA降低 MN疾病。因此，我一直保持NINDS R 01资金，以支持我的SBMA研究， 2000年，并持有NINDS R 01基金，以支持我的HD研究自2010年以来。在此期间，我 研究越来越多地集中于确定用于开发治疗的靶点和途径。作为 R35接受者，我将继续我对polyQ神经变性的细胞和分子基础的研究， 拥抱机会，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一个主要的焦点将是通过骨骼肌的运动来确定SBMA肌肉驱动的MN疾病的基础。 SBMA模型小鼠的肌肉和NMJ转录组分析和干细胞建模以重现非细胞 自发性SBMA MN变性。我还打算通过确定 PPARd在CNS中的正常功能并定义PPARd活化如何实现神经保护。我要跟从 令人兴奋的发现将PPARd神经保护与神经元活性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钝化是否可以改善HD表型。 由于PPARd在小胶质细胞中高度表达并抑制神经炎症，我将研究PPARd在小胶质细胞中的功能。 小胶质细胞和测试PPARd失调是否在神经退行性疾病中起作用。R35融资 为我提供了灵活性，以追求新颖的，雄心勃勃的研究polyQ疾病，扩大我的研究 计划涵盖发病机制的新兴领域，并保持对翻译的持久承诺， 神经变性的研究和治疗发展。

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.