Disease modifying pathways in Niemann-Pick type C disease

Niemann-Pick C 型疾病的疾病修饰途径

• 批准号: 8022914
• 负责人: Matthew J Elrick
• 金额: $ 2.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022914
• 关键词: Alzheimer' s Disease; Ataxia; Autophagocytosis; Biological Assay; Birth; Cell physiology; Cells; Child; Childhood; Cholesterol; Clinical; Critiques; Cytoplasmic Organelle; Cytoplasmic Protein; Data; Defect; Degradation Pathway; Development; Disease; Fibroblasts; Frontotemporal Dementia; Genes; Genetic; Glycolipids; Glycosphingolipids; Goals; Hereditary Disease; Human; Impaired cognition; Individual; Knockout Mice; Knowledge; Lead; Lipids; Liver Dysfunction; Lysosomes; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Deficit; Neurologic Dysfunctions; Neurologic Symptoms; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Positioning Attribute; Process; Proteins; Public Health; Role; Seizures; Severities; Severity of illness; Sirolimus; Supraoptic Vertical Ophthalmoplegia; Tauopathies; Teenagers; Testing; Update; Work; base; cholesterol trafficking; defined contribution; disease phenotype; early childhood; effective therapy; experience; improved; in vivo; insight; late endosome; lipid transport; meetings; mouse model; mutant; neuronal survival; neuropathology; new therapeutic target; novel therapeutic intervention; null mutation; progressive neurodegeneration; public health relevance; response; tau Proteins; tau mutation; therapeutic target

DESCRIPTION (provided by applicant): Niemann-Pick C disease is an autosomal recessive neurodegenerative disorder of childhood for which there is currently no effective treatment. This disorder results from deficiency of the intracellular cholesterol trafficking proteins NPC1 or NPC2, leading to the accumulation of cholesterol and glycolipids in late endosomes and lysosomes. How this cellular defect leads to neurodegeneration remains largely unknown. Processes compensating for pathologic lipid storage to promote neuronal survival represent promising therapeutic targets; however these are likewise not well understood. The objective of this application, therefore, is to identify cellular pathways that modulate the severity of neurodegeneration in Niemann-Pick C disease. This application is guided by preliminary data demonstrating that autophagy, a bulk degradation pathway for cytoplasmic proteins and organelles, is up-regulated in Niemann-Pick C disease. Additionally, our data demonstrate that deletion of the microtubule-associated protein tau markedly increases phenotypic severity of the Niemann-Pick C mouse model and impairs autophagy in NPC1-deficient cells. My central hypothesis is that the induction of autophagy and the presence of tau pathology are modifying factors in the pathogenesis of Niemann-Pick C disease. In my first Aim, I will establish the role of autophagy in modulating the severity of Niemann-Pick C disease, and evaluate autophagy as a therapeutic target. This will be accomplished by genetically inhibiting and pharmacologically enhancing autophagy in Niemann-Pick C mice, and assessing the effect of these manipulations on the disease phenotype. In my second Aim, I will define the contribution of tau to neurological dysfunction in Niemann-Pick C disease. I hypothesize that functional tau is required for increased autophagy in NPC1 deficient cells. I will use multiple assays to monitor the induction and flux of the autophagic pathway in NPCI/tau double-mutant primary neuronal cultures, and test the ability of wild type and mutant human tau to rescue autophagic defects in these cells. Further, I will determine the ability of human tau to rescue autophagic defects and the phenotype of Niemann-Pick C mice in vivo. The public health relevance of the proposed studies is that they will evaluate autophagy as a therapeutic target in Niemann-Pick C disease, and will elucidate the role of tau in neuropathology, thus improving our understanding of neurodegeneration in Niemann-Pick C and other tauopathies, including Alzheimer disease and the frontotemporal dementias. NOTE: The critiques of individual reviewers are provided in the following sections in an essentially unedited, verbatim form. They are provided to illustrate the range of opinions expressed. The application was discussed and assigned an overall score by all reviewers present. The critiques and the criterion scores were posted prior to the review meeting and may have not been updated or revised subsequent to the discussion at the meeting. Therefore, they may not represent the positions of the reviewers at the close of group discussion nor the final majority opinion of the group. The Resume and Summary of Discussion (above) represents the final outcome of the group discussion.

描述(申请人提供)：尼曼-皮克C病是一种儿童常染色体隐性遗传性神经退行性疾病，目前还没有有效的治疗方法。这种疾病是由于细胞内胆固醇转运蛋白NPC1或NPC2的缺乏，导致胆固醇和糖脂在晚期内体和溶酶体中积聚。这种细胞缺陷如何导致神经退化在很大程度上仍不清楚。补偿病理性脂肪储存以促进神经元存活的过程代表着有希望的治疗靶点；然而，这些同样还没有被很好地理解。因此，这项应用的目的是确定调节Niemann-Pick C病神经变性严重程度的细胞通路。这一应用是由初步数据指导的，该数据表明，自噬是细胞质蛋白质和细胞器的一种批量降解途径，在Niemann-Pick C病中上调。此外，我们的数据显示，微管相关蛋白tau的缺失显著增加了Niemann-Pick C小鼠模型的表型严重性，并损害了NPC1缺陷细胞的自噬。我的中心假设是，自噬的诱导和tau病理的存在是Niemann-Pick C病发病机制的修正因素。在我的第一个目标中，我将确定自噬在调节Niemann-Pick C病严重程度中的作用，并评估自噬作为治疗目标。这将通过在Niemann-Pick C小鼠中通过基因抑制和药物增强自噬，并评估这些操作对疾病表型的影响来实现。在我的第二个目标中，我将定义tau在Niemann-Pick C病神经功能障碍中的作用。我推测，在NPC1缺陷细胞中，功能tau是增加自噬所必需的。我将使用多种检测方法来监测Npci/tau双突变原代神经元培养中自噬途径的诱导和流向，并测试野生型和突变型人tau修复这些细胞中自噬缺陷的能力。此外，我将确定人类tau修复自噬缺陷的能力和体内Niemann-Pick C小鼠的表型。 拟议研究的公共卫生意义在于，他们将评估自噬作为Niemann-Pick C病的治疗靶点，并将阐明tau在神经病理学中的作用，从而提高我们对Niemann-Pick C和其他神经病变(包括阿尔茨海默病和额颞痴呆)中神经变性的理解。 注：以下各节以基本上未经编辑的逐字形式提供了对个别审查员的批评。提供它们是为了说明所表达的意见的范围。所有在场的评审员都对这份申请进行了讨论，并给出了总分。这些批评意见和标准分数是在审查会议之前张贴的，在会议讨论之后可能没有更新或修订。因此，它们可能不代表审查员在小组讨论结束时的立场，也不代表小组的最终多数意见。讨论摘要(上图)为小组讨论的最终结果。