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G PROTEIN SIGNALING IN OSTEOBLASTS

成骨细胞中的 G 蛋白信号传导

基本信息

批准号：
7334720
负责人：
Robert Nissenson
金额：
$ 32.19万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7334720
关键词：
Address Agonist Alleles Apoptosis Biology Bone Development Bone Marrow Bone Resorption Catalytic Domain Cells Complex Doctor of Philosophy Engineering Event Excision Fluorides G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetic Growth Growth Factor Homeostasis Hormones Knock-out Lead Ligands Light Link Mechanics Mediating Mus Nature Numbers Osteoblasts Osteogenesis Osteoporosis Pathway interactions Personal Satisfaction Pertussis Toxin Physiological Play Regulation Research Personnel Role Signal Pathway Signal Transduction Signaling Protein Skeletal system Skeleton Staging Stimulus Stromal Cells Strontium System Testing Transgenic Mice bone calcium phosphate in vivo interest loss of function novel strategies novel therapeutics programs receptor response therapeutic target transcription factor

项目摘要

Extrinsic factors such as hormones, growth factors, and mechanical strain produce their effects on skeletal growth and remodeling via actions on osteoblasts. Accordingly, there is great interest in defining how specific intracellular signaling pathways mediate the effects of these factors in controlling osteoblast function. G protein signaling occurs in response to many skeletal stimuli, and the consequence of this signaling depends on the nature of the G protein; the temporal delivery of the signal; and the phenotypic state of the osteoblast. A clearer understanding of how calciotropic agents such as PTH elicit their complex effects in bone requires studies that address these issues directly in an in vivo context. In the present proposal, we will assess the role of Gs and Gi signaling in osteoblasts in mediating anabolic skeletal responses. In one approach, novel G protein-coupled receptors termed RASSLs will be targeted to osteoblasts in transgenic mice. RASSLs activate specific G protein pathways in response to administration of synthetic agonists. Activation of Gs- and Gi RASSLs will allow us to dissect the role of these pathways in skeletal responses. In a second approach, Gs and Gi function will be ablated in osteoblasts in vivo by cre-mediated excision of functional Gs-alpha alleles and by targeted expression of the catalytic subunit of pertussis toxin, respectively. We will determine the effects of ablating these signaling pathways on normal skeletal homeostasis and on the anabolic response to PTH. Mechanistic studies will be carried out to assess the effects of G protein signals on osteoblast proliferation and apoptosis in vivo and in bone marrow stromal cells (BMSCs) isolated from the transgenic mice. Convergence of G protein signals with two pathways recently shown to be essential for bone formation - the LRP/canonical wnt pathway and the recently identified RSK2/ATF4 pathway- will be explored in BMSCs. We propose to: 1) assess the role of osteoblast Gs and Gi signaling in the regulation of skeletal homeostasis in mature mice. We will determine the effects of regulated, intermittent Gs and Gi signaling in osteoblasts at different stages of differentiation; determine the skeletal effect of conditional knockout of Gs and Gi signaling; and assess the mechanisms by which manipulation of Gs and Gi signaling elicits these effects; and 2) determine the contribution of Gs and Gi signaling to the anabolic response to PTH and the mechanisms of these effects. These studies will shed new light on the control of bone formation and bone resorption by G protein signaling in osteoblasts at different stages of differentiation. They may also provide new links between G protein signals and anabolic effects in bone, thereby identifying new therapeutic targets for the treatment of osteoporosis. LAY DESCRIPTION: We will explore how activation of specific signals in bone-forming cells can lead to increases in bone mass. The results may lead to new approaches to the treatment of osteoporosis.

激素、生长因子、机械应变等外在因素对骨骼产生影响