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.

项目总结/摘要 在我们对内体途径及其对病理学的功能性影响的理解方面存在着关键的差距。 神经退行性疾病如阿尔茨海默病（AD）和AD相关性痴呆（ADRD）的发生。 这项研究的首要目标是建立一个独立的研究计划，致力于阐明 神经变性的细胞机制和发现新的治疗靶点。本次亲- 这也揭示了导致Christianson综合征神经变性的内体功能障碍， 以建立与相关神经退行性疾病如AD/ADRD的机制联系。功能丧失 Na +/H+交换器6（NHE6）的突变导致称为Christianson syn. 综合征（CS），其呈现tau相关的神经退行性病理。我们最近发布了一个新的 一项描述一种新型CS大鼠模型的研究，该模型比目前的模型更能代表神经退行性特征。 小鼠模型核心假设是NHE6缺失损害晚期内体功能，这可能导致 与AD/ADRD相关的疾病。这项研究的基本原理是建立一个更好的理解缺陷， 可能作为CS和AD/ADRD的致病中心的活性内体途径。加上我最近 通过已发表的工作和初步数据，越来越多的证据强调了NHE 6在AD/ADRD中的功能。前- 扩大我们对NHE6介导的内体途径的了解将加速新的 CS和AD/ADRD的治疗靶点。该提案将采取多学科方法，包括： 先进的成像方法。在指导K99阶段，NHE6的丢失破坏ax- 将定义中性转运（Aim 1）和晚期内体成熟（Aim 2）。将执行目标1和目标2 在Eric Morrow博士的指导下，他是内溶体细胞生物学和罕见神经元疾病领域的领导者， 遗传性疾病包括CS。我的顾问团队将带来独特和互补的技能和知识， 这将进一步加强我的训练。在K99阶段，我将提高我在先进的超- 分辨率显微镜（SRM）成像和扩大我的知识内溶体细胞生物学和神经变性， 特别是AD/ADRD。我将利用这些获得的技能和知识来执行R00目标 （Aim3），其将确定NHE6缺失对转基因AD大鼠模型中AD/ADRD病理学的影响。 这一建议在方法和概念上都是创新的。它将利用SRM和新的大鼠模型， 在基因和生理上比老鼠更接近人类。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，这个提议将使我 获得严格的科学训练，在两个神经细胞生物学和神经变性，通过强 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计划， 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。