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The Mechanisms of Bone Mass Regulation by FIP200

FIP200 调节骨量的机制

基本信息

批准号：
9118872
负责人：
Fei Liu
金额：
$ 34.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118872
关键词：
Adult Autophagocytosis Biological Blood Bone Density Bone Development Bone Diseases Calvaria Cell Lineage Cell physiology Cells Complex Defect Degradation Pathway Development Disease Disease model Embryo Embryonic Development Excision Family Future Genes Glucocorticoids Goals Growth Health Homeostasis Human Interruption Knock-out Knockout Mice Knowledge Lesion Malignant Neoplasms Mammalian Cell Measures Membrane Metabolic Mitochondria Molecular Mus Neonatal Nutrient Nutritional Organelles Osteoblasts Osteoporosis Osteoporotic PTK2 gene Pathogenesis Pathway interactions Patients Perinatal Phenotype Play Population Proteins Public Health Reactive Oxygen Species Regulation Role Signal Pathway Signal Transduction Signaling Molecule Sirolimus Skeletal Development Staging Starvation Tissues Transgenic Mice Ubiquitin Vascular blood supply Woman age group aged base bone bone cell bone health bone loss bone mass bone metabolism cell type genetic approach improved in vivo inhibitor/antagonist knock-down men mouse model mutant novel novel therapeutics osteoblast differentiation postnatal prevent research study response skeletal treatment planning

项目摘要

DESCRIPTION (provided by applicant): The long term goal of the proposed studies is to understand the mechanisms of cell signaling in the regulation of key cellular functions in skeletal development/disease. In this proposal, we focus on the role of FIP200 (FAK-family Interacting Protein of 200 kDa) in the regulation of osteoblast differentiation. FIP200 was initially identifie as a novel FAK and Pyk2 inhibitor. Recently, FIP200 was identified as an essential component of mammalian autophagy. Despite our knowledge about FIP200 as a key signaling node in both embryogenesis and cancer development, it is unknown to what extent FIP200 regulates bone metabolism. In our preliminary studies, we found: 1. FIP200 conditional knockout in osteoblasts led to a severe osteopenic phenotype; 2. Osteoblast differentiation was greatly impaired in FIP200-null primary osteoblast cultures; 3. Primary calvarial osteoblasts have active basal and high inductive autophagy activity. However, FIP200 null primary calvarial osteoblasts expressing GFP-LC3 failed to form punctuate membrane structures in response to starvation and rapamycin treatment, indicating that FIP200 null osteoblasts had autophagy deficiency; 4. FIP200-null osteoblasts had large ubiquitin-positive aggregates, another indication of defective autophagy in these cells; and 5. Early neonatal FIP200 Osx-CKO mice had significant growth retardation in response to naturally occurring starvation as a result of sudden loss of maternal blood supply. Therefore, we hypothesize that FIP200 regulates bone mass through its regulation on osteoblast autophagy. The overall objective of the proposed project is to determine the molecular mechanisms and signaling pathways by which FIP200 regulates osteoblast function and bone mass using a combination of molecular, cell biological and mouse genetic approaches. The specific aims of this proposal are: Aim 1. To determine to what extent FIP200 regulates osteoblast function through its autophagic role. Aim 2. To elucidate the mechanism by which FIP200 regulates early postnatal bone development. Aim 3. To determine the role of FIP200 in bone homeostasis in adult mice. Health relevence: As a major public health threat, osteoporosis is present in an estimated 44 million men and women aged 50 and older, which represents 55 percent of the population in that age group in the USA. The proposed study with unique mouse disease model is highly valuable for determining the molecular and cellular mechanisms of pathogenesis of osteoporosis. It will allow us to define a novel bone mass regulation mechanism by autophagy, which is fundamentally important for the development of new therapeutics to treat bone diseases including osteoporosis. 1

描述(申请人提供)：拟议研究的长期目标是了解细胞信号在调节骨骼中关键细胞功能中的机制。发展/疾病。在这项研究中，我们关注FIP200(200 kDa的FAK家族相互作用蛋白)在成骨细胞分化调控中的作用。FIP200最初被鉴定为一种新的FAK和PYK2抑制剂。最近，FIP200被认为是哺乳动物自噬的重要组成部分。尽管我们知道FIP200在胚胎发育和癌症发展中都是一个关键的信号节点，但我们还不清楚FIP200在多大程度上调节骨代谢。在我们的初步研究中，我们发现：1.在成骨细胞中，FIP200条件敲除导致严重的骨量减少表型；2.在FIP200缺失的原代成骨细胞培养中，成骨细胞的分化受到严重损害；3.原代颅骨成骨细胞具有活跃的基础和高诱导自噬活性。然而，表达GFP-LC3的FIP200缺失的原代颅骨成骨细胞在饥饿和雷帕霉素处理后未能形成点状的膜结构，表明FIP200缺失的成骨细胞存在自噬缺陷；4.FIP200缺失的成骨细胞有大量泛素阳性聚集体，这是这些细胞自噬缺陷的另一个迹象；以及5.新生早期的FIP200 OSX-CKO小鼠由于母体血液供应的突然丧失，对自然发生的饥饿有显著的生长迟缓反应。因此，我们推测FIP200通过对成骨细胞自噬的调节来调节骨量。该项目的总体目标是结合分子、细胞生物学和小鼠遗传学方法，确定FIP200调节成骨细胞功能和骨量的分子机制和信号通路。本提案的具体目的是：目的1.确定FIP200通过其自噬作用在多大程度上调节成骨细胞的功能。目的2.阐明FIP200调控生后早期骨发育的机制。目的3.探讨FIP200在成年小鼠骨稳态中的作用。健康相关性：骨质疏松症是一种主要的公共健康威胁，估计有4400万50岁及以上的男性和女性患有骨质疏松症，占美国该年龄段人口的55%。这种独特的小鼠疾病模型的研究对于确定骨质疏松症发病的分子和细胞机制具有重要的价值。这将使我们能够通过自噬来定义一种新的骨量调节机制，这对于开发治疗包括骨质疏松症在内的骨骼疾病的新疗法是至关重要的。1