Temporal-spatial Regulation of MSCs by IGF-1

描述（由申请人提供）：骨质疏松症是一种主要的骨骼疾病，在衰老过程中影响男性和女性。其发病机制不仅是由于骨吸收中的破骨细胞活性增加，而且由于老年人成骨细胞供应不足而导致骨形成减少。成骨细胞是来源于间充质干细胞（MSC）谱系的非复制细胞。我们假设，骨量在儿童期获得、成年期维持以及随着年龄增长而丢失的模式是由于成骨细胞的可用性降低，因为MSCs随着年龄增长而失去/减缓了向成骨细胞分化的能力。已知胰岛素样生长因子1 （IGF-1）通过激活哺乳动物雷帕霉素靶来刺激成骨细胞分化，以维持适当的骨微结构和质量。因此，一系列的实验和动物模型被设计来证实MSC分化随着年龄的增长而减慢，这是由IGF-1信号通路的下调介导的。第一个目的是利用MSC谱系追踪小鼠模型，确定青年、成年和老年小鼠中MSC分化为成熟成骨细胞的时空调节。第二个目标是剖析IGF-1信号通路在生命周期中是如何被调节的，并影响msc的命运。提出的研究的目标是确定在分化过程中的速率限制步骤，以便未来

DESCRIPTION (provided by applicant): Osteoporosis is a major bone disorder that affects both men and women during aging. The pathogenesis is not only due to the increased osteoclast activity in bone resorption, but also a decrease in bone formation mostly attributed to an insufficient supply of osteoblasts in the aged. Osteoblasts are non-replicative cells derived from the mesenchymal stem cell (MSC) lineage. We hypothesize that the pattern of acquisition of bone mass during childhood, maintenance in adulthood, and loss with aging is due to decreased osteoblast availability for bone formation as MSCs lose/slow their ability to differentiate into osteoblasts with aging. Insulin like growth factor type 1 (IGF-1) is known to stimulate osteoblastic differentiation by activation of mammalian target of rapamycin to maintain proper bone microarchitecture and mass. Thus, a series of experiments and animal models are designed to confirm the hypothesis that MSC differentiation slows with aging, mediated by down- regulation of the IGF-1 signaling pathway. The first aim is to determine the temporal-spatial regulation of MSC differentiation into mature osteoblasts in young, adult, and old mice using a MSC lineage tracing mouse model. The second aim is to dissect how the IGF-1 signaling pathway is regulated during the lifespan and affects the fate of MSCs. The goal of the proposed study is to identify the rate limiting steps in the differentiation process so that future therapies can be targeted at these essential steps. This project will be conducted by Dr. Janet Crane under the guidance of Dr. Xu Cao in the Department of Orthopaedic Surgery at Johns Hopkins University. Dr. Crane, a Pediatric Endocrinologist, is dedicated to a career in academia using basic and translational research to study factors affecting bone formation. Dr. Cao has an exceptional research career in bone biology using in vivo mouse models to study signaling mechanisms by which bone marrow MSCs contribute to bone homeostasis and remodeling, which will provide Dr. Crane with the training necessary to initiate her career as an independent investigator. The available resources and strong ongoing collaborative arrangements within the Department of Orthopaedic Surgery, the Division of Pediatric Endocrinology, and the Department of Neuroscience provide a rich learning environment and are completely supportive of the academic advancement of Dr. Crane.