Therapeutic targets for Niemann-Pick type C neurodegeneration

工作说明书 本申请寻求对R01 NS122746的补充支持，标题为 Niemann-Pick C型神经退行性变的目标“以促进与健康相关的多样性 研究。本附录的目的是为了支持博士生阿黛尔·科雷亚的培训 参加了密歇根大学的生物医学科学课程。科雷亚女士的论文 该项目的重点是C型尼曼-皮克病(NPC)，这是一种总是致命的常染色体隐性遗传 影响各个年龄段的脂肪储存障碍。患者出现临床上的异质性表型 这包括严重的进行性神经变性、肝肿大和过早死亡。全国人大是 通常由NPC1基因功能丧失突变引起(95%的病例)，编码一种 晚期输出未酯化胆固醇所需的多通道跨膜糖蛋白 内质体和溶酶体。尽管我们对NPC1在疾病中的作用有了新的理解 细胞内胆固醇运输，鼻咽癌的诊断仍然特别黯淡。确实有 目前还没有FDA批准的疾病修改疗法，患者大多死于童年， 既反映了我们目前对疾病发病机制的认识上的差距，也反映了一个重大的未满足的 医疗需要。我们的长期目标是为疾病改良的发展作出贡献 鼻咽癌患者的治疗。实现这一目标的下一步是追求总目标 父母R01拨款：定义中枢神经系统疾病发病机制的关键靶点 被毒品开发工作所利用。我们将利用遗传学、生物化学、组织学和 表型分析：确定神经元脂质储存和毒性的程度 被优化的合成高密度脂蛋白纳米粒拯救(目标1)；确定少突胶质细胞的作用 鼻咽癌神经病理学中的谱系细胞(目标2)；并建立蛋白平衡调节剂对鼻咽癌的影响 人性化的NPC1模式系统(目标3)。本补编中提出的工作是一个延伸。 母公司R01拨款的目标1。在这里，我们建议研究人工合成的治疗益处。 高密度脂蛋白纳米粒在人类诱导的神经元中表达一种常见的致病变异体 NPC1(I1061T NPC1)。对细胞存活、脂肪储存和基因表达的有益影响 被量化。最有希望的配方将在一种新的鼻咽癌小鼠模型上进行测试 表达人I1061T NPC1。对疾病表型的影响，包括行为 异常、存活、神经元脂肪储存和基因表达变化将被量化。 这些研究有望建立针对细胞内脂类存储的优化方法 合成的高密度脂蛋白将改善疾病的表型。

STATEMENT OF WORK This application seeks supplemental support for R01 NS122746, entitled “Therapeutic targets for Niemann-Pick type C neurodegeneration” to promote diversity in health-related research. The goal of this supplement is to support the training of Adele Correia, a PhD trainee enrolled in the Program in Biomedical Sciences at the University of Michigan. Ms. Correia’s thesis project focuses on Niemann-Pick disease type C (NPC), an invariably fatal autosomal recessive lipid storage disorder affecting all ages. Patients develop a clinically heterogeneous phenotype that includes severe, progressive neurodegeneration, hepatomegaly, and early death. NPC is commonly caused by loss-of-function mutations in the NPC1 gene (95% of cases), encoding a multipass transmembrane glycoprotein required for exporting unesterified cholesterol from late endosomes and lysosomes. Despite our emerging understanding of the role of NPC1 in intracellular cholesterol trafficking, a diagnosis of NPC remains particularly bleak. There are currently no FDA-approved disease modifying therapies and patients most often die in childhood, reflecting both gaps in our current knowledge of disease pathogenesis and a significant unmet medical need. Our long-term goal is to contribute toward the development of disease-modifying therapies for NPC patients. The next step in attaining this goal is to pursue the overall objective of the parent R01 grant: to define critical targets in CNS disease pathogenesis that can be exploited by drug development efforts. We will use genetic, biochemical, histological, and phenotypic analyses to: establish the extent to which neuronal lipid storage and toxicity are rescued by optimized synthetic HDL nanoparticles (Aim 1); determine the role of oligodendrocyte lineage cells in NPC neuropathology (Aim 2); and establish effects of proteostasis regulators in humanized NPC1 model systems (Aim 3). The work proposed in this supplement is an extension of Aim 1 of the parent R01 grant. Here, we propose to study the therapeutic benefits of synthetic HDL nanoparticles in human induced neurons expressing a common disease-causing variant of NPC1 (I1061T NPC1). Beneficial effects on cell survival, lipid storage, and gene expression will be quantified. The most promising formulation will be tested in a new mouse model of NPC which expresses human I1061T NPC1. Effects on disease phenotypes including behavioral abnormalities, survival, neuronal lipid storage, and gene expression changes will be quantified. These studies are expected to establish that targeting intracellular lipid storage using optimized synthetic HDLs will ameliorate disease phenotypes.