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.

项目摘要/摘要 在我们对内体途径及其对病程的功能影响的理解上存在严重的差距。 神经退行性疾病的发生，如阿尔茨海默病(AD)和AD相关痴呆(ADRD)。 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 神经退行性变的细胞机制和发现新的治疗靶点。这项计划的目的是- POSAL也揭示了导致克里斯汀森综合征神经变性的内体功能障碍 以建立与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)的突变导致一种名为Christian syn-1的内体神经系统疾病。 Drome(CS)，呈现tau相关的神经退行性病变。我们最近出版了一本新的 研究描述了一种新的CS大鼠模型，该模型比目前的CS更能反映神经退行性变的特征 老鼠模型。中心假说是，NHE6缺失会损害晚期的内体功能，这可能会导致- 导致AD/ADRD相关的病理改变。这项研究的基本原理是建立对失败的更好的理解- 可能在CS和AD/ADRD中起致病枢纽作用的主动内体通路。和我最近的 已发表的工作和初步数据，越来越多的证据强调了NHE6在AD/ADRD中的作用。前- 我们对NHE6介导的内体途径的了解将加速鉴定新的 CS和AD/ADRD的治疗靶点。这项提案将采取多学科方法，包括 先进的成像方法。在指导的K99阶段，NHE6的丢失扰乱了AX- ONAL转运(AIM1)和内体晚期成熟(AIM2)将被定义。将执行AIM1和AIM2 在埃里克·莫罗博士的指导下，埃里克·莫罗博士是内多体细胞生物学和罕见神经- 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，我将提升我在高级超级- 分辨率显微镜(SRM)成像，拓宽了我在内殖体细胞生物学和神经退行性变方面的知识- 发作性障碍，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病理的影响。 这项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，作为大鼠 在基因和生理上都比老鼠更接近人类。此外，它还将完善我们目前对NHE6的看法 功能和揭示神经退行性疾病的内体功能障碍。总体而言，这项提议将使我 在神经细胞生物学和神经退行性变方面获得严格的科学培训 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，名为- 用于阐明神经退行性疾病和其他与衰老相关的疾病的细胞机制。