Genetic & Epi-Genetic Regulation of Muscle Regeneration

描述(由申请人提供)： 这位候选人计划通过开发新技能和对复杂的DNA修复科学的深刻理解来补充她在干细胞生物学领域的成就。为了实现这一目标，候选人将利用在DNA修复领域享有盛名的菲尔·哈纳瓦特博士的帮助，以及汤姆·兰多博士提供的动态研究环境。在最初的指导期内获得的知识、技能和合作将促进独立调查员在新的科学领域的职业生涯。从科学上讲，该奖项将深入了解正常组织和衰老组织中的祖细胞生物学，并在组织修复方面提供新的实用解决方案。这项工作将描述调控骨骼肌再生的分子机制，并将研究为什么修复会随着年龄的增长而恶化。成年肌肉由于卫星细胞的活动而再生。随着年龄的增长，再生能力和肌肉力量减弱，与炎症相关的病理改变增加。根据初步数据，卫星细胞的生物学是由Notch和Wnt通路控制的，这些通路在年轻的肌肉细胞中活跃，而在老年肌肉细胞中不活跃。这项拟议的工作将研究为什么在老年肌肉损伤后，肌肉再生所需的Notch和Wnt信号缺乏。假说是，在成年肌肉(由终末分化的肌管和静止的卫星细胞组成)中，许多基因保持沉默，由于非转录位点的DNA修复效率不高，这些基因的DNA损伤会随着时间的推移而积累。当这些先前沉默的基因被激活以响应肌肉损伤时，累积的DNA损伤干扰转录，导致细胞功能丧失。我们将研究肌肉细胞是否会随着年龄的增长积累DNA损伤，并将测试DNA修复停滞或分化相关的下降与损伤诱导的Notch和Wnt途径成员表达之间的潜在分子联系。为了配合这一主要研究目标，我们将对肌肉损伤激活的基因进行年轻和年老的基因阵列分析，以便为DNA修复研究提供更多的候选基因，并寻找新的调控肌肉再生的基因。这项工作将有助于理解出生后的肌肉发生，并可能对促进成人组织的再生具有治疗价值。

DESCRIPTION (provided by applicant): The candidate plans to complement her achievements in the field of stem cell biology by developing new skills and a profound understanding of the complex science of DNA repair. To achieve this goal, the candidate will use help of Dr. Phil Hanawalt, renown in the field of DNA repair and a dynamic research environment provided by Dr. Tom Rando. The knowledge, skills and collaborations obtained during the initial mentored period will facilitate the career of an independent investigator in the new field of science. Scientifically, this award will give insight into the biology of progenitor cells in normal and aged tissues and provide novel practical solutions in tissue repair. This work will characterize the molecular mechanisms regulating regeneration of skeletal muscle and will investigate why repair deteriorates with age. Adult muscle regenerates due to the activity of satellite cells. With age, the regeneration capacity and muscle strength diminish and inflammatory-related pathologies increase. Biology of satellite cells is controlled, based on preliminary data, by the Notch and Wnt pathways that are active in young muscle cells, but not in old. The proposed work will study why Notch and Wnt signaling that are required for muscle regeneration are lacking after injury in aged muscle. The hypothesis is that in the adult muscle (comprised of terminally differentiated myotubes and quiescent satellite cells), many genes remain silent, and since DNA repair is not efficient in non-transcribed loci, DNA damage accumulates with time in these genes. When these previously silent loci are activated in response to muscle injury, the accumulated DNA damage interferes with transcription and results in the loss of cell function. We will investigate if muscle cells accumulate DNA damage with age and will test a potential molecular link between a quiescence- or differentiation-related decline in DNA repair and the injury-induced expression of Notch and Wnt pathway members. Complimenting this main research goal, we will perform a young-versus-old gene array analysis of genes activated by muscle injury in order to provide more candidates for the DNA repair studies and to identify novel genes regulating muscle regeneration. This work will help to understand postnatal myogenesis and is likely to have therapeutic value for the enhancement of regeneration in adult tissues.