Mesenchymal Stem Cells as Determinants of Tissue Aging

项目摘要/摘要 老年骨骼肌出现脂肪和纤维性渗出导致肌肉功能下降 以及代谢紊乱的增加。然而，缓解这一有害过程的手段仍然存在。 缺乏导致这些物质在肌肉内积累的细胞和分子机制 不良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(MSCs) 占据骨骼肌间隙的间质间充质干细胞(interstitic MSCs，iMSCs)一直被认为是 肥胖症和纤维化的最重要的细胞介质。在年轻的组织中，iMSCs不会转化为这些命运，但 相反，它们仍然是祖细胞，并被认为支持组织动态平衡和 再生。我们假设，iMSCs的命运决定了它们对骨骼肌的影响，并且随着年龄的增长， 间充质干细胞成为对整个生物体产生负面影响的脂肪细胞和纤维细胞。在对…的研究中 在这项提议中，我们将从基因上定义iMSCs在肌肉内脂肪和纤维化渗透中的作用。 以体内细胞为靶点，在衰老骨骼肌模型中检测其发育潜力(目标1)。 我们还将确定iMSCs在骨骼肌内稳和再生中的必要性。 通过在体内特异性地耗尽iMSCs，然后检测这些活动(目标2)，来老化环境。最后，我们会 通过在体外对iMSC命运进程进行建模并使用高级 RNA测序技术揭示可功能调节的非编码和编码RNA物种 细胞命运决定(目标3)。我们的首要目标是阐明iMSC的命运对骨骼的影响 并利用这些发现开发治疗靶点，以减轻与年龄相关的骨骼肌 拒绝。 候选人迈克尔·沃斯奇纳博士在实验祖细胞生物学和 花了十多年时间研究干细胞相关疾病。在该奖项的指导阶段， 沃斯奇纳博士的目标是在与年龄相关的干细胞衰退和大规模并行方面推进他的知识。 用于揭示决定命运的遗传途径的技术。沃斯奇纳博士的导师和合作伙伴- 导师托马斯·兰多博士和朱迪思·坎皮西博士分别在这些方面拥有全面的专业知识 区域。他们将为沃斯奇纳博士提供一个丰富的环境，使其发展成为一名杰出的独立人士 老龄化研究的调查员。

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.