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Neuronal microtubule regulation and aging

神经元微管调节与衰老

基本信息

批准号：
10488174
负责人：
Lizhen Chen
金额：
$ 31.41万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10488174
关键词：
Address Affect Age Age of Onset Aging Alleles Alzheimer&apos s Disease Animals Architecture Axon Biochemical Biological Process Caenorhabditis elegans Cells Cytoskeleton Data Defect Dendrites Development Disease Elements Functional disorder Gap Junctions Genes Genetic Goals Growth Intervention Lead Link Lipids Longevity MAP4 Maintenance Measures Metabolic Pathway Metabolism Microtubule Polymerization Microtubule Stabilization Microtubule-Associated Proteins Microtubules Mitotic Molecular Monitor Morphology Mutation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Orthologous Gene Peripheral Play Positioning Attribute Process Proteins Regulation Reporting Risk Factors Role Signal Transduction Structure Testing Time Tissues Transgenes Transgenic Organisms Tubulin age effect age related age related neurodegeneration base confocal imaging experimental study genetic approach healthy aging imaging approach in vivo insight lipid metabolism lipidomics loss of function mutant neuron loss neuronal cell body normal aging novel optogenetics preservation tau Proteins tool

项目摘要

PROJECT SUMMARY (Neuronal microtubule regulation and its autonomous and non-autonomous effects on aging) Aging is the greatest risk factor for developing neurodegenerative diseases including Alzheimer's Disease (AD). Neuronal aging, defined as a progressive loss of function and structure, predisposes neurons to degeneration. The importance of microtubule (MT) regulation in neurons is underscored by the critical role of MT-associated proteins, e.g. tau and tau-like proteins, whose dysfunction leads to neurodegeneration. Surprisingly, little is known about the role of MTs in the normal aging process. MT regulation is involved on several levels of neuronal function and maintenance of structure, and MT regulation also appears to be a general downstream indicator and effector in age-dependent neurodegeneration. The cause and effect relationship between MT defects and cellular dysfunction is not clear. In C. elegans, it has been demonstrated that mutations in protein with tau-like repeats (ptl-1), an ortholog of tau/MAP2/MAP4, leads to defective neuronal function and an accelerated occurrence of age-associated morphological changes. On the other hand, it has also been shown that mutations in other MT regulators delay the onset of age-related changes. These data show defects in MTs are not only associated with, but also contribute to, neuronal aging. The goals of this proposed study are to define changes in MT status associated with neuronal aging and to characterize mechanisms by which MT defects affect neuronal function. Preliminary data indicate mutations in multiple MT regulators are sufficient to influence lipid metabolism and lifespan. The central hypothesis is preservation of MT polymerization in neurons delays neuronal aging and promotes longevity through gap junctions. In Aim 1, we will test whether loss of MT polymerization causes neuronal aging. In Aim 2, we will test whether neuronal MT perturbation regulates longevity and peripheral lipid metabolism via gap junctional signaling. Confocal imaging, molecular, biochemical and C. elegans genetic approaches will be used to fulfil these aims. Data generated from this proposal will not only increase our understanding of the roles played by MT regulation in the neuronal and organismal aging, but also potentially lead to novel targets to delay aging and its associated diseases.

项目总结