NHE6-mediated endosomal defects in neurodegenerative disorders

NHE6 介导的神经退行性疾病中的内体缺陷

• 批准号: 10592044
• 负责人: Eugene Y Lee
• 金额: $ 12.13万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592044
• 关键词: Acceleration; Advisory Committees; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Award; Axon; Axonal Transport; Biochemical; Cellular biology; Christianson syndrome; Cytoplasmic Tail; Data; Dedications; Defect; Deposition; Disease; Endosomes; Functional disorder; GTPase-Activating Proteins; Genes; Genetic study; Goals; Histologic; Human; Impairment; Knowledge; Link; Lysosomes; Mediating; Mentors; Mentorship; Methodology; Methods; Microscope; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Phase; Phenocopy; Physiological; Process; Proteins; Protons; Publishing; Rattus; Reporting; Research; Resources; Swelling; Testing; Time; Training; Transgenic Organisms; Work; X Chromosome; axonal degeneration; endosome lumen; imaging modality; innovation; interdisciplinary approach; late endosome; live cell imaging; loss of function mutation; microscopic imaging; mouse model; nervous system disorder; neurogenetics; neuron loss; new therapeutic target; novel; programs; retrograde transport; skill acquisition; skills; tau Proteins; tau-1; therapeutic target; training opportunity; ultra high resolution

PROJECT SUMMARY/ABSTRACT There are critical gaps in our understanding of the endosomal pathway and its functional impact on the patho- genesis of neurodegenerative disorders such as Alzheimer’s disease (AD) and AD-related dementia (ADRD). The overarching goal of this study is to build an independent research program dedicated to elucidating the cellular mechanisms of neurodegeneration and discovering novel therapeutic targets. The objective of this pro- posal is to reveal the endosomal dysfunction that causes neurodegeneration in Christianson syndrome, as well as to establish mechanistic links to related neurodegenerative disorders such as AD/ADRD. Loss-of-function mutations in Na+/H+Exchanger 6 (NHE6) cause an endosomal neurological disorder called Christianson syn- drome (CS), which presents tau-associated neurodegenerative pathologies. We have recently published a new study describing a novel rat model of CS, which better represents neurodegenerative features than the current mouse model. The central hypothesis is that NHE6 deletion impairs late endosomal function, which may contrib- ute to AD/ADRD-related pathologies. The rationale for this study is to establish a better understanding of defec- tive endosomal pathways which may act as a pathogenic hub in CS and AD/ADRD. Together with my recently published work and preliminary data, mounting evidence emphasizes the function of NHE6 in AD/ADRD. Ex- panding our knowledge of the NHE6-mediated endosomal pathway will accelerate the identification of novel therapeutic targets for CS and AD/ADRD. This proposal will take multidisciplinary approaches including ad- vanced imaging methods. During the mentored K99 phase, mechanisms whereby the loss of NHE6 disrupt ax- onal transport (Aim1) and late endosomal maturation (Aim2) will be defined. Aim1 and Aim2 will be performed under the guidance of Dr. Eric Morrow, who is a leader in the field of endolysomal cell biology and rare neuro- genetic disorders including CS. My advisory team will bring unique and complementary skills and knowledge, which will further enhance my training. During the K99 phase, I will boost my expertise in advanced super- resolution microscope (SRM) imaging and broaden my knowledge in endolysomal cell biology and neurodegen- erative disorders, especially AD/ADRD. I will utilize these acquired skills and knowledge to perform the R00 aim (Aim3), which will determine the impact of NHE6 deletion on AD/ADRD pathology in a transgenic AD rat model. This proposal ise methodologically and conceptually innovative. It will utilize SRM and novel rat models, as rats are more genetically and physiologically closer to humans than mice. Also, it will refine our current view of NHE6 function and reveal endosomal dysfunction in neurodegenerative disorders. Overall, this proposal will allow me to acquire rigorous scientific training in both neuronal cell biology and neurodegeneration through the strong mentorship and research program. This award will enable me to launch an independent research program ded- icated to elucidating cellular mechanisms of neurodegenerative diseases and other aging-related disorders.

项目概要/摘要 我们对内体途径及其对病理的功能影响的理解存在重大差距 阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD) 等神经退行性疾病的起源。 本研究的总体目标是建立一个独立的研究计划，致力于阐明 神经退行性变的细胞机制和发现新的治疗靶点。这个亲的目标 posal 的目的是揭示导致克里斯蒂安森综合征神经变性的内体功能障碍 建立与 AD/ADRD 等相关神经退行性疾病的机制联系。功能丧失 Na+/H+交换器 6 (NHE6) 的突变会导致称为 Christianson Syn- 的内体神经系统疾病 drome (CS)，呈现 tau 相关的神经退行性病理。我们最近发布了一个新的 研究描述了一种新型 CS 大鼠模型，该模型比目前的模型更好地代表了神经退行性特征 鼠标模型。核心假设是 NHE6 缺失会损害晚期内体功能，这可能会导致 AD/ADRD 相关病理。这项研究的目的是为了更好地了解缺陷 内体途径可能作为 CS 和 AD/ADRD 的致病中心。连同我最近 已发表的工作和初步数据表明，越来越多的证据强调 NHE6 在 AD/ADRD 中的功能。前任- 扩大我们对 NHE6 介导的内体途径的了解将加速新的鉴定 CS 和 AD/ADRD 的治疗靶点。该提案将采取多学科方法，包括广告 先进的成像方法。在指导的 K99 阶段，NHE6 的丢失破坏了 ax- 机制。 将定义内运输（Aim1）和晚期内体成熟（Aim2）。将执行 Aim1 和 Aim2 在内溶体细胞生物学和罕见神经细胞领域的领导者 Eric Morrow 博士的指导下 遗传性疾病，包括 CS。我的顾问团队将带来独特且互补的技能和知识， 这将进一步加强我的训练。在K99阶段，我将提升我在高级超级方面的专业知识 分辨率显微镜（SRM）成像并拓宽我在内溶体细胞生物学和神经退行性疾病方面的知识- 活动障碍，尤其是 AD/ADRD。我将利用这些获得的技能和知识来实现​​ R00 目标 (Aim3)，这将确定 NHE6 缺失对转基因 AD 大鼠模型中 AD/ADRD 病理学的影响。 该提案在方法论和概念上都是创新的。它将利用 SRM 和新型大鼠模型，如大鼠 与小鼠相比，它们在遗传和生理上更接近人类。此外，它将完善我们目前对 NHE6 的看法 功能并揭示神经退行性疾病中的内体功能障碍。总的来说，这个建议将使我 通过强大的能力获得神经细胞生物学和神经变性方面严格的科学培训 指导和研究计划。这个奖项将使我能够启动一个独立的研究项目，旨在- 致力于阐明神经退行性疾病和其他衰老相关疾病的细胞机制。