权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Establishment of a human, age-specific model for axon growth and regeneration studies

建立用于轴突生长和再生研究的人类特定年龄模型

基本信息

批准号：
9978418
负责人：
Darcie Leann Moore
金额：
$ 44.1万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2020-05-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978418
关键词：
ASCL1 gene Adult Affect Age Animal Model Animals Axon Behavior Biological Birth Bypass Cell Aging Cell Culture System Cell Maintenance Cells Clinical Trials Communities DNA Damage Development Doxycycline Embryo Encyclopedia of DNA Elements Environment Epigenetic Process Expression Profiling Fibroblasts Gene Expression Genes Genetic Transcription Glutamates Growth Homologous Gene Human In Vitro Injury Knock-out Lead Length Life Maintenance Measures Medical Methods Mitochondria Modeling Motor Neurons Mus Natural regeneration Neonatal Neuraxis Neurons PTEN gene Paralysed Pathway interactions Phenotype Play Population Protocols documentation Research Research Personnel Resources Rodent Role Somatic Cell Spinal cord injury System Testing Treatment Efficacy Validation Work aged axon growth axon regeneration cell age disability excitatory neuron human model human tissue in vitro Model induced pluripotent stem cell juvenile animal knock-down novel overexpression pluripotency postnatal psychologic regenerative response screening social stem cells targeted treatment telomere therapeutic target tool transcription factor transdifferentiation young adult

项目摘要

Human spinal cord injury leads to life-long disability, with limited treatment options despite decades of research in rodents. Recent evidence indicates that there are fundamental differences in gene expression between human and mouse, suggesting a critical need for identification of novel or human-specific candidates as targets to increase axon regeneration following spinal cord injury. Additionally, in vitro studies of axon growth are typically performed in neurons from embryonic or young postnatal rodents, ages with increased intrinsic growth ability, and a very different transcriptional landscape from adult neurons. Thus, we propose to create an age-relevant, human model for axon growth and regeneration. Recent technological advances now allow for human adult somatic cells to be reprogrammed into stem cells, and then differentiated into neurons. However, reprogramming these cells through pluripotency has been shown to erase the “age” of the original cell, resulting in a more embryonic identity of the resulting neuron. Using a direct reprogramming protocol, we will transdifferentiate neonatal, ~35 year old, and ~70 year old human somatic cells directly into neurons through overexpression of specific neuronal factors, allowing for maintenance of the cell’s biological age identity. We will determine the maintenance of age in these cells at the level of the epigenetic age signature, gene expression, and markers of cellular aging. As the first study of axon growth in age-maintained human neurons, we will characterize the basal axon growth behavior on permissive and inhibitory substrates to identify if age plays a role in human axon growth ability. To test this new resource, we will target 20 different genes and pathways previously identified in other species to regulate axon growth for their conservation in function in human neurons. In rodents it has recently been shown that certain axon growth modifiers such as PTEN knockout, do not function similarly in aged animals as young animals (Geoffroy et al, 2016). Thus, we will utilize our age-maintained human iNs to determine if age drives changes in axon growth phenotypes. Completion of this research will 1) establish a new human, age-relevant cell culture system for axon growth studies, 2) identify genes and their regulators that have conserved functions in human neurons, and 3) determine the role age plays in axon growth ability. Identification of translational targets specifically in human neurons ultimately may lead to the development of effective therapeutic targets for human spinal cord injury.

人类脊髓损伤导致终身残疾，尽管几十年来，治疗选择有限