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
- 来源:
- 关键词:G protein coupled receptor kinase SDS polyacrylamide gel electrophoresis arrestins autocrine bone metabolism cell differentiation cell growth regulation cell proliferation confocal scanning microscopy epidermal growth factor genetically modified animals hormone receptor hormone regulation /control mechanism immunoaffinity chromatography laboratory mouse metalloendopeptidases mitogen activated protein kinase osteoblasts paracrine parathyroid hormones phosphorylation physiologic bone resorption polymerase chain reaction prostaglandin receptor receptor coupling western blottings
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: