Genetic & Epi-Genetic Regulation of Muscle Regeneration

描述（由申请人提供）： 候选人计划通过发展新技能和对DNA修复复杂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，候选人将利用菲尔·哈纳沃特博士的帮助，在DNA修复领域的声誉和汤姆·兰多博士提供的动态研究环境。在最初的指导期间获得的知识，技能和合作将有助于独立调查员在新的科学领域的职业生涯。作为科学家，该奖项将深入了解正常和老化组织中祖细胞的生物学，并为组织修复提供新的实用解决方案。这项工作将表征调节骨骼肌再生的分子机制，并将研究为什么修复随着年龄的增长而恶化。成人肌肉再生由于卫星细胞的活动。随着年龄的增长，再生能力和肌肉力量减弱，炎症相关的病理增加。根据初步数据，卫星细胞的生物学是由Notch和Wnt通路控制的，这两条通路在年轻的肌肉细胞中很活跃，但在老年肌肉细胞中不活跃。拟议的工作将研究为什么肌肉再生所需的Notch和Wnt信号在老年肌肉损伤后缺乏。假设是在成人肌肉（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，并且由于DNA修复在非转录基因座中无效，DNA损伤在这些基因中随着时间的推移而积累。当这些先前沉默的基因座响应于肌肉损伤而被激活时，累积的DNA损伤干扰转录并导致细胞功能丧失。我们将研究肌肉细胞是否随着年龄的增长而积累DNA损伤，并将测试DNA修复的静止或分化相关下降与Notch和Wnt通路成员损伤诱导的表达之间的潜在分子联系。为了补充这一主要研究目标，我们将对肌肉损伤激活的基因进行基因阵列分析，以便为DNA修复研究提供更多的候选基因，并确定调节肌肉再生的新基因。这项工作将有助于了解出生后的肌肉发生，并可能有治疗价值的成人组织再生的增强。

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.