Parathyroid Hormone and Osteoblast Mitogenesis

甲状旁腺激素和成骨细胞有丝分裂

基本信息

  • 批准号:
    6435366
  • 负责人:
  • 金额:
    $ 33.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-09-15 至 2006-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Osteoblasts regulate the deposition of bone matrix protein and its subsequent mineralization. In situ, regulation of osteoblast proliferation, differentiation and function occurs via the complex interplay of extracellular signals mediated by steroid hormone and vitamin D receptors, receptor tyrosine kinases, and G protein-coupled receptors (GPCRs), such as those for parathyroid hormone (PTH) and prostaglandins. While it is clear that GPCRs transmit signals that are critical for the regulation of osteoblast metabolism, their significance as potential regulators of osteoblast growth and differentiation has only recently been appreciated. The broad goal of this research proposal is to determine how GPCRs regulate the growth and differentiation of osteoblasts through activation of the ERK mitogen-activated protein kinase (MAP) cascade, a key regulatory pathway in terms of both cell proliferation and differentiation. We provide preliminary data that demonstrate that GPCRs employ two novel mechanisms to direct the temporal and spatial activation of MAP kinases. First, matrix metalloprotease-mediated ectodomain shedding causes the release of autocrine ligands that induce "transactivation" of epidermal growth factor receptors (EGFRs). Second, beta-arrestins, proteins which bind to agonist-occupied GPCRs and uncouple them from their cognate G proteins, function as scaffolds for the component kinases of the ERK cascade and lead to the targeted activation of MAP kinase within specific cellular compartments. The first Aim of this proposal is to characterize the molecular mechanisms whereby PTH and prostaglandin receptors regulate the activity of MAP kinase cascades in osteoblasts. The second Aim is to determine the role of EGFR and beta-arrestin-dependent signals in regulating osteoblast proliferation, differentiation, and matrix production in vitro. These studies will employ osteoblastic cell lines and primary cultures of osteoblasts from mice in which EGFR or beta-arrestin function has been selectively inhibited. The third Aim of the proposal is to determine the role of EGFR and beta-arrestin-dependent signals in the control of anabolic bone metabolism by PTH in vivo. These studies will employ transgenic mouse models, in which beta-arrestins have been knocked out by homologous recombination or EGFR function has been impaired through osteoblast-specific expression of a dominant inhibitory mutant EGFR. By increasing our understanding of the mechanisms of GPCR signaling in bone, these studies may permit the rational development of safe strategies for employing PTH analogues to modulate osteoblast number and/or function.
描述(申请人提供):成骨细胞调节沉积

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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LOUIS M LUTTRELL其他文献

LOUIS M LUTTRELL的其他文献

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{{ truncateString('LOUIS M LUTTRELL', 18)}}的其他基金

Pharmacodynamics of Biased G Protein-Coupled Receptor Agonism
偏向 G 蛋白偶联受体激动的药效学
  • 批准号:
    9916766
  • 财政年份:
    2018
  • 资助金额:
    $ 33.09万
  • 项目类别:
Pharmacodynamics of Biased G protein-Coupled Receptor Agonism
偏向 G 蛋白偶联受体激动的药效学
  • 批准号:
    8879161
  • 财政年份:
    2013
  • 资助金额:
    $ 33.09万
  • 项目类别:
Pharmacodynamics of Biased G protein-Coupled Receptor Agonism
偏向 G 蛋白偶联受体激动的药效学
  • 批准号:
    8578152
  • 财政年份:
    2013
  • 资助金额:
    $ 33.09万
  • 项目类别:
Pharmacodynamics of Biased G protein-Coupled Receptor Agonism
偏向 G 蛋白偶联受体激动的药效学
  • 批准号:
    8680259
  • 财政年份:
    2013
  • 资助金额:
    $ 33.09万
  • 项目类别:
Fluorometric Imaging Plate Reader (FLIPRtetra)
荧光成像板读取器 (FLIPRtetra)
  • 批准号:
    7794548
  • 财政年份:
    2010
  • 资助金额:
    $ 33.09万
  • 项目类别:
Tyrosine Kinases in G Protein Mediated Signaling
G 蛋白介导的信号转导中的酪氨酸激酶
  • 批准号:
    8004390
  • 财政年份:
    2010
  • 资助金额:
    $ 33.09万
  • 项目类别:
STUDIES IN INFANTS FOR THE IMMUNOPATHOGENSIS OF T1D
婴儿 T1D 免疫发病机制研究
  • 批准号:
    7719625
  • 财政年份:
    2008
  • 资助金额:
    $ 33.09万
  • 项目类别:
Parathyroid Hormone and Osteoblast Mitogenesis
甲状旁腺激素和成骨细胞有丝分裂
  • 批准号:
    6924562
  • 财政年份:
    2002
  • 资助金额:
    $ 33.09万
  • 项目类别:
Parathyroid Hormone and Osteoblast Mitogenesis
甲状旁腺激素和成骨细胞有丝分裂
  • 批准号:
    6820556
  • 财政年份:
    2002
  • 资助金额:
    $ 33.09万
  • 项目类别:
Parathyroid Hormone and Osteoblast Mitogenesis
甲状旁腺激素和成骨细胞有丝分裂
  • 批准号:
    6654915
  • 财政年份:
    2002
  • 资助金额:
    $ 33.09万
  • 项目类别:
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