Mechanism of STING-mediated Neuropathology in Niemann-Pick Disease

C型尼曼-匹克病(NPC)是一种致命性神经退行性疾病，由基因突变引起。 NPC1(95%)和NPC2(5%)基因。鼻咽癌的神经学特征与阿尔茨海默病有惊人的相似之处 阿尔茨海默病(AD)，导致一些专家认为鼻咽癌是“儿童阿尔茨海默氏症”。没有FDA批准的治疗方法 是可用的。与鼻咽癌疾病相关的血脂和胆固醇缺陷是众所周知的。然而， 鼻咽癌疾病中神经炎症和浦肯野细胞死亡的免疫途径尚不清楚。 我们最近发现，鼻咽癌基因缺失和基因缺失会激活先天免疫刺痛通路 小鼠的刺痛通路成分能够显著挽救鼻咽癌的神经病理。的总目标是 这个项目是为了了解刺痛如何驱动与鼻咽癌疾病相关的神经病理。目标1将 重点放在细胞内的机制上，在那里我们将剖析NPC缺乏如何激活STING信号。 目标2将专注于脑组织病理学，在那里我们将全面确定刺痛表达细胞 鼻咽癌疾病的类型、活动及其功能贡献。目标3将专注于治疗评估， 在那里我们将用现有的和新的STING途径治疗NPC1-/-小鼠和NPC1患者IPSC来源的细胞 抑制剂。斯汀与包括帕金森氏症在内的几种神经退行性疾病有关， ALS/FTD，现在是NPC1。这里提出的研究将提供亟需的全面了解 刺痛通路在大脑中的作用以及从刺痛激活到 神经病理学。

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disease caused by genetic mutations in the NPC1 (95%) and NPC2 (5%) genes. Neurological features of NPC bear striking resemblances with Alzheimer’s disease (AD), leading to some experts considering NPC as “Childhood Alzheimer’s”. No FDA-approved therapy is available. Lipids and cholesterol defects associated with the NPC disease are well understood. However, immune pathways underlying neuroinflammation and Purkinje cell death in the NPC disease remain unknown. We recently found that the innate immune STING pathway is activated by NPC-deficiency, and genetic deletions of STING pathway components in mice are able to remarkably rescue NPC neuropathology. The overall goal of this project is to understand how STING drives neuropathology associated with the NPC disease. Aim 1 will focus on intracellular mechanisms, where we will dissect how STING signaling is activated by NPC-deficiency. Aim 2 will focus on brain tissue pathology, where we will comprehensively determine STING expression cell types, activities and their functional contribution to the NPC disease. Aim 3 will focus on therapeutic assessment, where we will treat Npc1-/- mice and NPC1 patient iPSC-derived cells with existing and new STING pathway inhibitors. STING has been implicated in several neurodegenerative diseases including Parkinson’s disease, ALS/FTD and now NPC1. Studies proposed here will provide a much-needed comprehensive understanding of STING pathway function in the brain as well as a step-by-step mechanism from STING activation to neuropathology.