INVESTIGATING THE ROLE OF THE CYTOSKELETON IN NEURODEGENERATION

研究细胞骨架在神经变性中的作用

• 批准号: 10534590
• 负责人: Morgan Catherine Stephens
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534590
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Actins; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; American; Automobile Driving; Autophagocytosis; Behavior; Behavioral; Biochemical; Biological Assay; Biological Models; Brain; Cause of Death; Cell model; Cells; Clinical; Color; Communication; Complex; Cytoskeleton; Data; Dementia; Dendritic Spines; Deposition; Development; Disease; Disease Progression; Distal; Drosophila genus; Environment; Etiology; Genes; Genetic; Genetic Screening; Goals; Harvest; Histologic; Histology; Human; Human Cell Line; Huntington Disease; Impairment; In Vitro; LIM Domain; LIMK1 gene; Lysosomes; Malignant Neoplasms; Measures; Mediating; Microfilaments; Microscopy; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phase; Phosphotransferases; Prevalence; Process; Proteins; Regulation; Research; Resolution; Rod; Role; Senile Plaques; Societies; Synapses; System; Tauopathies; Techniques; Therapeutic; Therapeutic Intervention; Transmission Electron Microscopy; Ubiquitin; United States; Vesicle; Western Blotting; actin depolymerizing factor; attenuation; brain tissue; cofilin; combat; density; depolymerization; disability; extracellular; histological studies; hyperphosphorylated tau; improved; in vitro Assay; in vivo; induced pluripotent stem cell; insight; knock-down; misfolded protein; mouse model; multicatalytic endopeptidase complex; nerve stem cell; neurodegenerative phenotype; neuroinflammation; neuropathology; neurotoxic; new therapeutic target; novel; overexpression; prevent; protein aggregation; protein degradation; proteostasis; response; tau Proteins; tau aggregation; therapeutic development; therapeutic target; trafficking; vesicle transport; wasting

Project Summary/Abstract: Neurodegenerative diseases are among the fastest growing clinical burdens on society, and in the next 20 years Alzheimer’s Disease (AD) is projected to overtake cancer as the second leading cause of death in adults. Despite AD prevalence, there are currently no therapeutic interventions to combat the underlying pathology driving disease progression. While much is still not understood about neurodegenerative pathogenesis, the accumulation of extracellular amyloid- plaques and intracellular tau tangles are undisputed hallmarks of AD. To combat disease progression, an attractive therapeutic strategy is to investigate impairments in native proteostatic mechanisms used to dispose of this neurotoxic protein accumulation. One such mechanism which has been implicated in the development and progression of not only AD, but numerous neurodegenerative proteinopathy disorders including Parkinson’s and Huntington’s disease, is the autophagy-lysosomal network (ALN). The ALN is a bulk degradative system utilizing vesicular transport to dispose of large protein aggregates which contribute to neuronal dysfunction. This process relies on the active remodeling of the actin cytoskeleton to initiate, capture, and transport neurotoxic cargo for degradation and maintain proper proteostasis. However, mechanistically how dysregulations in cytoskeletal dynamics are associated with neurodegenerative pathology contributing to disease remains unclear. Through multiple behavioral neurodegenerative screens, we have identified an actin depolymerizing factor, cofilin, along with its upstream molecular regulators, which upon modulation improve neurodegenerative behavioral deficits and lower tau accumulation in vivo. This proposal seeks to investigate how cytoskeletal dynamics contribute to AD through genetic attenuation of the cofilin-centric cytoskeletal remodeling pathway. I hypothesize that modulating the activity of cofilin and its regulators will ameliorate AD neurodegenerative phenotypes via modification of the cytoskeleton and proteostasis. Aim 1 will utilize behavioral and histological approaches to investigate how genetic modulation of numerous genes within the remodeling pathway influence neurodegenerative phenotypes in tauopathy Drosophila and mouse models. In Aim 2, I will investigate mechanistically how this cytoskeletal remodeling pathway is involved in the formation and progression of the ALN through 1) measuring changes in neurotoxic protein accumulation upon cytoskeletal genetic modulation using various tauopathy model systems, and 2) utilizing high resolution microscopy techniques in AD patient derived induced pluripotent stem cells (iPSCs) along with biochemical in vitro assays, to investigate how genetically modulating cofilin disrupts various phases of the ALN. Upon successful completion of this project, we will identify molecular impairments of cytoskeletal remodeling associated with neurodegeneration that are involved in proteostatic imbalances and disease pathogenesis. Furthermore, we hope to identify novel therapeutic targets within this pathway capable of treating not only AD, but multiple neurodegenerative diseases caused by neurotoxic protein accumulation.

项目摘要/摘要： 神经退行性疾病是社会增长最快的临床负担之一，在接下来的20年中 尽管如此，阿尔茨海默氏病（AD）仍将超过癌症作为成人的第二大死亡原因。 广告患病率，目前尚无治疗性干预措施来应对较低的病理驾驶 疾病进展。 AD的细胞外淀粉样板和细胞内Tau缠结的积累也是无与伦比的标志 战斗疾病进展，一种有吸引力的治疗策略是研究天然蛋白质抑制 用于处置这种神经毒性蛋白积累的机制。 与发育和程序性神经退行性蛋白硫硫醇有关 包括帕金森氏病和亨廷顿氏病在内的疾病是自噬 - 溶酶体网络（ALN） 是利用囊泡转运来处理大蛋白质聚集体的批量降解系统 神经元功能障碍。 并运输神经毒性货物以降解并维持蛋白质。 细胞骨架动力学的失调与导致的神经退行性病理有关。 疾病尚不清楚。 解聚因子Cofilin，以及ISTream分子调节剂，在调节后改善 神经退行性的行为缺陷和较低的tau在体内积累。 细胞骨架动力学如何通过以Cofilin为中心的细胞骨架的遗传衰减来促进AD 我假设调节cofilin的活性和调节剂的途径 通过修饰细胞骨架和蛋白质的AD神经退行性表型。 行为和组织学方法研究了如何在 重塑途径会影响果蝇和小鼠模型中的神经退行性表型 AIM 2，我将从机械上研究THOS细胞骨架重塑途径如何参与形成 ALN至1）测量细胞骨架上神经毒性蛋白积累的变化 使用各种tauopathy模型系统的遗传调制，2）使用高分辨率显微镜 AD患者衍生诱导的多能干细胞（IPSC）的技术以及生化的体外测定 为了研究遗传调节Cofilin在成功压缩时如何破坏ALN的各个阶段 在这个项目中，我们将确定与与之相关的细胞骨架重塑的分子损伤 与蛋白质失衡和疾病发病机理有关的神经变性。 希望在该途径中识别能够不仅可以治疗AD，而且多重治疗的途径中的新型治疗靶 由神经毒性蛋白积累引起的神经退行性疾病。