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，我发现 X连锁脊髓和延髓肌萎缩症(SBMA)的原因是CAG重复序列在 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)重复区域，这一发现导致了一个新领域的出现。我的研究项目始于 重点关注两种多项智力障碍：SBMA和脊髓小脑性共济失调7型(SCA7)。我早期的工作确立了 转录异常是PolyQ病发病机制中的关键因素。我发起了对亨廷顿氏症的研究 疾病(HD)，并将HD的线粒体功能障碍和代谢缺陷与转录失调联系起来 转录共激活子PGC-1a。2016年，我记录了PPARd和Hunting之间的交互 (HTT)蛋白在HD小鼠的纹状体样神经元和大脑皮层中表达，我证明了PPARd 抑制是HD神经毒性的原因之一。这些发现使我重新调整了选择性和强大的PPARd的用途 激动剂KD3010能够挽救HD转基因小鼠和中等刺神经元中HTT的神经毒性 来自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 通过在BAC条件下从骨骼肌中切除突变型AR转基因 转基因小鼠阻止神经肌肉SBMA表型的发展，确立了重要性 SBMA下段神经肌肉接头(NMJ)的骨骼肌-运动神经元(MN)通讯 MN病。因此，我一直保持着NINDS R01的资金，以支持我的SBMA研究 自2010年以来，我一直持有NINDS R01基金来支持我的高清研究。在这段时间内，我的 研究的重点越来越多地放在确定目标和开发疗法的途径上。作为一名 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， 抓住机会将我们的发现扩展到更常见的神经退行性疾病，包括阿尔茨海默病， 警察局和肌萎缩侧索硬化症。一个主要的焦点将是确定SBMA肌肉驱动的MN疾病通过骨骼的基础 SBMA模型小鼠肌肉和NMJ转录组分析及干细胞模型概括非细胞 自主性SBMA MN变性。我也打算继续研究房屋署和PPARD，以确定 PPARd在中枢神经系统中的正常功能，并确定PPARd激活如何实现神经保护。我会跟着去的 将PPARd神经保护与神经元活性依赖基因调控联系起来的令人兴奋的发现 并将测试钝化快速主要反应基因表达是否可以改善HD表型。 由于PPARd在小胶质细胞中高表达并抑制神经炎症，我将研究PPARd在 并测试PPARd失调是否在神经退行性疾病中起作用。R35资金将 给我提供了灵活性，让我可以继续进行新的、雄心勃勃的多Q病研究，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 神经退行性变的研究和治疗进展。

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.