Complement Components as Mediators of Cell and Tissue Aging

项目总结/摘要 与年龄相关的细胞功能变化受到局部和全身环境的影响，其中 细胞驻留。这已经被异时性研究明确地证明，在这些研究中，老化细胞被 引入或暴露于更年轻的环境，导致细胞功能增强，使人联想到 更年轻的同行。相反，暴露在老化环境中的年轻细胞采用更老化的细胞。 表型。这些发现都指向可能深刻影响细胞衰老的循环因素。在 研究这一建议，我们寻求扩展我们自己的发现，从研究中出现的异时 涉及由一种或多种全身性因子介导的活性Wnt信号传导的联体小鼠， 肌肉干细胞（MuSC）衰老。后来的研究表明，补体级联反应的一个成分C1 q， 随着年龄的增长，在血液中增加，能够激活细胞中的Wnt信号传导，并负责年龄- 相关的肌肉再生障碍，虽然没有确定的细胞目标。C1 q有 随后被证明在多种生理过程中独立于经典级联发挥作用， 来驱动各种组织的老化。在研究这项建议时，我们会探讨机制 C1 q通过探索相关的细胞靶点和信号级联来抑制肌肉再生 C1 q活动为了实现这些目标，本提案的具体目标是：（1）通过以下方式研究该机制： 哪种C1 q促进了与年龄相关的肌肉再生潜力下降（特别是MuSC 是直接靶点）;（2）测试C1 q是否通过诱导TGFβ信号传导促进细胞衰老（基于 我们和其他人在以前的研究中获得的证据表明，该途径是Wnt信号传导的下游 和MuSC老化的介质）;和（3）测试C1 q是否促进骨骼肌中年龄相关的纤维化。 通过直接作用于纤维脂肪生成祖细胞（FAP）来研究肌肉的细胞机制。 证明了C1 q在促进肌肉纤维化中的作用）。这些研究将扩大我们的 了解这种细胞衰老的系统介质的作用和机制，以及令人兴奋的新发现。 补体成分的非经典机制的发现及其在组织中的新发现的作用 衰老

PROJECT SUMMARY/ABSTRACT Age-related changes in cellular functions are influenced by the local and systemic environment in which a cell resides. This has been demonstrated unequivocally by heterochronic studies in which aged cells are introduced or exposed to a more youthful environment, resulting in enhanced cellular function reminiscent of more youthful counterparts. Conversely, young cells exposed to an aged environment adopt a more aged phenotype. These findings all point to circulating factors that may profoundly influence cellular aging. In the studies of this proposal, we seek to extend our own findings that emerged from studies of heterochronic parabiotic mice implicating active Wnt signaling, mediated by one or more systemic factors, as a driver of muscle stem cell (MuSC) aging. It was later shown that a component of the complement cascade, C1q, increased in the blood with age, is capable of activating Wnt signaling in cells, and is responsible for age- related impairment in muscle regeneration, although the cellular targets were not identified. C1q has subsequently been shown to function independent of the classic cascade in multiple physiologic processes and to drive aging in a variety of tissues. For the studies of this proposal, we will seek to explore the mechanisms by which C1q inhibits muscle regeneration by exploring the cellular targets and signaling cascades associated with C1q activity. Toward these goals, the Specific Aims of this proposal are (1) to study the mechanism by which C1q promotes the age-related decline in muscle regenerative potential (and specifically whether MuSCs are the direct target); (2) to test whether C1q promotes cellular aging by inducing TGFβ signaling (based on evidence we and others have obtained in previous studies of this pathway being downstream of Wnt signaling and a mediator of MuSC aging); and (3) to test whether C1q promotes age-related fibrogenesis in skeletal muscle by acting directly on fibroadipogenic progenitors (FAPs) (to examine the cellular mechanism of the demonstrated effects of C1q in promoting muscle fibrosis). Together, these studies will expand our understanding of the effects and mechanisms of this systemic mediator of cellular aging and the exciting new findings of non-canonical mechanisms of complement components and their newly discovered roles in tissue aging.