Mesenchymal Stem Cells as Determinants of Tissue Aging

项目总结/摘要 老年骨骼肌脂肪和纤维化浸润的出现导致肌肉功能下降 以及代谢紊乱的增加然而，仍然存在减轻这种有害过程的手段， 缺乏，因为细胞和分子机制，导致肌内积累这些 不利的非典型组织还没有被很好地理解。最近发现的间充质干细胞（MSC）， 占据骨骼肌的间质空间（间质MSC，iMSC）已经被假定为 最重要的是肥胖和纤维化的细胞介质。在年轻的组织中，iMSC不向这些命运转化，但 相反，保持为祖细胞，并被认为支持组织稳态的过程， 再生我们假设iMSC的命运决定了它们对骨骼肌的影响， iMSC成为脂肪细胞和纤维细胞，对整个生物体产生负面影响。研究中 在这项提议中，我们将通过遗传学方法来确定iMSC在肌内脂肪和纤维化浸润中的作用。 在体内靶向细胞并检查其在老化骨骼肌模型中的发育潜力（目的1）。 我们还将确定iMSC在年轻和年轻人骨骼肌稳态和再生中的必要性。 通过在体内特异性地消耗iMSC，然后检查这些活性，来研究衰老环境（目的2）。最后我们将 通过在体外模拟这一过程并使用先进的 RNA测序技术揭示了非编码和编码RNA种类，可以在功能上调节 细胞命运测定（Aim 3）。我们的首要目标是阐明iMSC命运对骨骼肌的影响。 并利用这些发现来开发治疗靶点，以减轻与年龄相关的骨骼肌 下降 候选人Michael Wosczyna博士在实验祖细胞生物学方面拥有丰富的专业知识， 花了十多年时间研究干细胞相关疾病。在这个奖项的指导阶段， 博士Wosczyna的目标是提高他在年龄相关的干细胞衰退方面的知识， 用于揭示决定命运的遗传途径的技术。沃希纳博士的导师和合作伙伴 导师，博士托马斯兰多和博士朱迪思坎皮西，分别在这些方面有全面的专业知识， 地区他们将为Wosczyna博士提供一个丰富的环境，使其成为一名杰出的独立人士。 衰老研究的研究员

Project Summary/Abstract The appearance of fatty and fibrotic infiltration in aged skeletal muscle causes a decline in muscle function and an increase in metabolic disorders. However, a means to mitigate this detrimental process remains absent, as the cellular and molecular mechanisms that lead to the intramuscular accumulation of these adverse atypical tissues are not well understood. Recently identified mesenchymal stem cells (MSCs) that occupy the interstitial space of skeletal muscle (interstitial MSCs, iMSCs) have been postulated as the foremost cellular mediators of adiposis and fibrosis. In young tissue iMSCs do not covert to these fates, but instead, remain as progenitors and are assumed to support the processes of tissue homeostasis and regeneration. We hypothesize that the fate of iMSCs determine their impact on skeletal muscle and with age, iMSCs become the adipocytes and fibrocytes that negatively impact the organism as a whole. In the studies of this proposal, we will define the role of iMSCs in intramuscular fatty and fibrotic infiltration by genetically targeting the cell in vivo and examining its developmental potential in models of aged skeletal muscle (Aim 1). We will also determine the necessity of iMSCs in skeletal muscle homeostasis and regeneration in young and aged milieus by specifically depleting iMSCs in vivo and then examining these activities (Aim 2). Finally, we will define the molecular pathways of iMSC fate progression by modeling this process in vitro and using advanced RNA sequencing technologies to reveal non-coding and coding RNA species that can functionally modulate cell fate determination (Aim 3). Our overarching goal is to elucidate the impact iMSC fate has on skeletal muscle and to leverage these findings to develop therapeutic targets to mitigate age-related skeletal muscle decline. The candidate, Dr. Michael Wosczyna, has extensive expertise in experimental progenitor cell biology and has spent more than a decade studying stem cell-related disorders. During the mentoring phase of this award, Dr. Wosczyna aims to advance his knowledge in age-related stem cell decline and in massively parallel technologies used for uncovering genetic pathways of fate determination. Dr. Wosczyna's mentor and co- mentor, Dr. Thomas Rando and Dr. Judith Campisi, respectively, have comprehensive expertise in these areas. They will provide an enriching environment for Dr. Wosczyna to develop as a prominent independent investigator in aging research.