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Targeting aging genes and pathways to promote optic nerve regeneration

针对衰老基因和途径促进视神经再生

基本信息

批准号：
10547815
负责人：
Mei Wan
金额：
$ 40.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547815
关键词：
ATAC-seq Aging Axon Bioinformatics Biomedical Research Blood Vessels Brain Caenorhabditis elegans Catalytic Domain Cell Aging Cells Central Nervous System Chromatin Chromosome Fragility Consensus Corticospinal Tracts Cytoskeleton DNA Repair Data Development Enzymes Epigenetic Process Evolution FOXO3A gene FRAP1 gene Failure Genes Genetic Techniques Genetic Transcription Genomic Instability Heterochromatin Histones IGF-1 Signaling Pathway Insulin Insulin-Like Growth Factor I Knock-out Longevity Lysine Mediating Methylation Molecular Molecular Target Myosin Type II Natural regeneration Nerve Regeneration Neurodegenerative Disorders Neurons Noise Nonmuscle Myosin Type IIA Nutrient Optic Nerve Optic Nerve Injuries PIK3CG gene Pathway interactions Process Production Protocols documentation Publishing RNA-Directed DNA Polymerase Regenerative capacity Regulation Regulator Genes Regulatory Pathway Rejuvenation Retinal Ganglion Cells Role SIRT1 gene SOX11 gene STK11 gene Sensory Signal Transduction Spinal cord injury TP53 gene Telomerase Traumatic Brain Injury age effect aging gene axon growth axon injury axon regeneration c-myc Genes cell regeneration designer receptors exclusively activated by designer drugs detection of nutrient experimental study gene repression genetic manipulation histone methylation human disease in vivo regeneration induced pluripotent stem cell inhibitor innovation insight neural novel optic nerve regeneration overexpression screening sensor spinal cord regeneration telomere transcription factor transcriptome sequencing transcriptomics

项目摘要

Summary To date, targeting the genes regulating intrinsic axon growth ability have produced by far the most promising results in optic nerve regeneration. Recent studies, including ours, have provided strong evidence that neuronal aging might be a key converging process underlying the loss of intrinsic axon growth ability of CNS neurons. Indeed, many genes that act to regulate axon regeneration are also hallmark genes of aging (genomic instability, telomere attrition, epigenetic alteration, and nutrient sensing, etc.). First, recent studies and our preliminary results showed that c-Myc and p53, two well-known genes involved in DNA repair and genomic instability during aging, act to support optic nerve regeneration. Second, our preliminary study showed that telomerase reverse transcriptase (TERT) was necessary for sensory axon regeneration in vivo. Third, aging is often associated with decreased methylation of histone 3 at lysine 27 (H3K27) and increased methylation of H3K4, resulting in reduced amount of heterochromatin. In support, the level of H3K27 demethylase UTX increases during aging and knocking out UTX in c. elegans promotes longevity. Our unpublished study showed that knocking out UTX and its targeted gene, Magi3, in RGCs drastically promoted optic nerve regeneration. Fourth, the insulin and IGF-1 signaling (IIS) pathways, the key regulators of nutrient sensing, are the most conserved aging controlling pathway in evolution. IGF-1 and many IIS downstream targets, such as Pten/PI3K, Akt, and mTor, are all important regulators of optic nerve regeneration. Our published study and a recent study have shown that Sirt1 and LKB1, two important nutrient sensors, function to regulate sensory axon and spinal cord regeneration, respectively. Foxo3, another key target of Akt signaling, has recently been shown to promote vascular cell regeneration through Sirt1. Lastly, recent findings indicated that cellular reprogramming process can reverse aging and rejuvenate the cells. Importantly, manipulations of several reprogramming factors, such as KLF4 and Lin28, have been shown to promote optic nerve regeneration. Therefore, we hypothesize that aging regulatory genes/pathways can be manipulated to promote optic nerve regeneration through rejuvenation of mature CNS neurons. In Aim 1, we will determine if manipulation of miR-138/Sirt1, TERT, and Foxo3 in RGCs can promote optic nerve regeneration. In Aim 2, we will first determine if combination of these aging genes with myosin II knockout or enhanced neural activity would have synergistic effects on regeneration. We will then use RNA-seq and ATAC-seq of purified RGCs to explore how these aging genes regulate optic nerve regeneration. In Aim 3, by performing RNA-seq and ATAC-seq of purified RGCs at different developing, maturation, and aging stages, we will first use advanced integrative bioinformatics analyses to identify top candidate aging genes and their associated transcription factors, both of which act to orchestrate RGCs aging. We will then perform functional screening experiments to determine their roles in regulation of axon growth and optic nerve regeneration.

总结