Temporal-spatial Regulation of MSCs by IGF-1

描述(申请人提供)：骨质疏松症是一种在衰老过程中影响男性和女性的主要骨骼疾病。其发病机制不仅是由于骨吸收过程中破骨细胞活性的增加，而且主要是由于老年人成骨细胞供应不足所致的骨形成减少。成骨细胞是来源于间充质干细胞(MSC)谱系的非复制性细胞。我们假设，儿童时期获得骨量，成年后保持，随着年龄增长而丧失的模式是由于随着年龄的增长，骨髓间充质干细胞失去/减缓其分化为成骨细胞的能力，成骨细胞用于骨形成的能力降低。已知胰岛素样生长因子-1(IGF-1)通过激活哺乳动物靶标雷帕霉素来刺激成骨细胞分化，以维持适当的骨微结构和质量。因此，设计了一系列实验和动物模型，以证实MSC分化随着年龄的增长而放缓的假设，这是通过下调IGF-1信号通路来实现的。第一个目的是利用MSC谱系追踪小鼠模型，确定年轻、成年和老年小鼠MSC分化为成熟成骨细胞的时空规律。第二个目的是剖析IGF-1信号通路在生命周期中是如何调控的，并影响MSCs的命运。拟议研究的目标是确定差异化过程中的速率限制步骤，以便未来 治疗可以针对这些基本步骤。该项目将由约翰·霍普金斯大学整形外科的徐曹医生指导，由珍妮特·克兰博士主持。克莱恩博士是一名儿科内分泌学家，他致力于学术界的职业生涯，利用基础研究和翻译研究来研究影响骨形成的因素。曹博士在骨生物学领域拥有卓越的研究生涯，利用活体小鼠模型研究骨髓间充质干细胞促进骨内稳态和骨重建的信号机制，这将为克兰博士提供必要的培训，开始她的独立研究生涯。骨科外科、儿科内分泌科和神经科学系的现有资源和持续的强有力的合作安排提供了丰富的学习环境，并完全支持克兰博士的学术进步。

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.