PRIMARY CILIA/CILIARY TRANSPORT IN BONE PATTERNING, GROWTH AND MECHANOSENSING

描述（由申请人提供）：这是一个探索性项目，目的是确定细胞和/或蛋白质上所谓的初级纤毛是否对骨骼发育和出生后生长至关重要。研究人员还提出了一项假设，即初级纤毛是骨骼组织对机械刺激的正常重塑反应所必需的。这些研究是由最近的发现推动的，即在蠕虫、苍蝇、老鼠和人类中，初级纤毛和与之相关的信号分子在许多细胞中充当受体，而编码初级纤毛蛋白质的基因突变除了会导致内脏异常外，还会导致骨骼缺陷。研究人员计划将小鼠的遗传和其他实验研究与培养的器官和细胞的生化分析结合起来，这些器官和细胞来自影响初级纤毛形成或功能的基因突变的小鼠。通过这些研究，研究者旨在确定(1)长骨生长板的形成和功能是否需要初级纤毛，(2)四肢骨骼正常形态的发育是否也需要初级纤毛，最后(3)骨骼组织对机械刺激的正常反应是否需要这些组织细胞上存在初级纤毛。这些研究可能会对骨骼发育和维护的机制以及调节骨骼对重力和运动反应的分子机制产生新的和令人兴奋的见解。这些研究可能有助于确定药物的新靶点，这些药物旨在逆转衰老和骨质疏松症期间骨物质的流失，或者可能加速骨物质过度积累疾病（如骨质疏松症）中骨质流失的药物。

DESCRIPTION (provided by applicant): This is an exploratory project with the goal of establishing whether so-called primary cilia on cells and/or proteins needed for their assembly and function are essential for skeletal development and postnatal growth. Work is also proposed to test the hypothesis that primary cilia are required for the normal remodeling response of skeletal tissues to mechanical stimulation. The studies are prompted by recent discoveries that primary cilia and signaling molecules associated with them serve as receptors on many cells, in worms and flies as well as in mice and humans, and that mutations in genes coding for proteins in primary cilia can cause skeletal defects in addition to abnormalities in internal organs. The investigators plan to combine genetic and other experimental studies in mice with biochemical analyses of cultured organs and cells derived from mice with mutations in genes that affect the formation or function of primary cilia. Through the studies, the investigators aim at establishing (1) whether primary cilia are needed for the formation and function of growth plates in long bones, (2) whether they also are needed for development of the normal pattern of bones in limbs, and finally, (3) whether the normal response of skeletal tissues to mechanical stimulation requires the presence of primary cilia on the cells in these tissues. The studies are likely to generate new and exciting insights into mechanisms for bone development and maintenance and the molecular machinery that regulates the response of bones to gravity and exercise. The studies may help define new targets for drugs aimed at reversing the loss of bone substance during aging and in osteoporosis or drugs that may accelerate bone loss in diseases with excess accumulation of bone substance, such as osteopetrosis.