Roles of Smad1 Dephosphorylation in Osteoblast Differentiation

Smad1 去磷酸化在成骨细胞分化中的作用

• 批准号: 8308683
• 负责人: XIN-HUA FENG
• 金额: $ 28.89万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308683
• 关键词: Area; Biochemical; Biological Process; Biology; Bone Development; Bone Diseases; Bone Growth; Bone Marrow; Bone Morphogenetic Proteins; Cell Differentiation process; Cell Nucleus; Cell physiology; Cells; Complex; Data; Development; Differentiation and Growth; Event; Gene Expression; Gene Targeting; Genomics; Goals; Health; Human; Investigation; Knock-out; Lead; MADH4 gene; Malignant Neoplasms; Mediating; Mesenchymal Differentiation; Mesenchymal Stem Cells; Molecular; Mus; Osteogenesis; Osteoporosis; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Prevention; Property; Protein Dephosphorylation; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Publishing; Pulmonary Hypertension; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Smad Proteins; Smad protein; Transducers; base; bone morphogenetic protein receptor type I; bone morphogenetic protein receptors; cell growth; human disease; insight; member; novel; novel therapeutic intervention; nucleocytoplasmic transport; osteoblast differentiation; receptor; research study; response; trafficking; transcription factor

DESCRIPTION (provided by applicant): Abrogation of cellular responses to Bone Morphogenetic Proteins (BMPs) and other members of TGF-( superfamily are associated with human bone diseases such as osteoporosis, pulmonary hypertension and heritable cancer. Our long-term objective is to understand the molecular basis of how BMP/TGF-( regulate cell growth and differentiation, and the underlying mechanisms through which alterations in BMP signaling leads to deregulation of growth and differentiation control in human bone diseases. BMPs induce the differentiation of mesenchymal cells towards the osteoblastic lineage to promote bone formation. One of the most critical events in activation of BMP signal transduction pathway is the phosphorylation of transcription factor Smad1/5/8 (collective term for Smad1, Smad5 and Smad8) by BMP receptors. While phosphorylated Smad1/5/8 directly activate the target genes in the nucleus, protein phosphatases are anticipated to dephosphorylate phospho-Smad1/5/8 and consequently inactivate BMP signaling. The identity of the long sought-after phosphatase has been one of the major unanswered questions in BMP/TGF-( biology until very recently. We have discovered that Smad1/5/8 can be dephosphorylated by several phosphatases. Our short-term strategy for this proposal is to characterize biochemical properties of the phosphatases and investigate their biological functions in the regulation of BMP signaling during osteoblast differentiation. Our preliminary studies (both published and unpublished) lead us to hypothesize that Smad phosphatases block or terminate BMP signaling during osteoblast differentiation. Thus, it is significantly important to investigate the physiological roles of Smad phosphatases in bone formation. In this application, we will focus our study on the functions and molecular mechanism of Smad dephosphorylation during osteoblast differentiation. Three specific aims are proposed: Aim 1: Biochemical characterization of Smad phosphatases for dephosphorylation of BMP-specific Smad1/5/8. Aim 2: Elucidation of the functions of Smad phosphatases-mediated Smad dephosphorylation in BMP signaling. Aim 3: Investigation on the roles of Smad phosphatases in osteoblast differentiation from mesenchymal stem cells. The proposed experiments will open a new area of research on how Smad phosphatases modulate BMP signaling pathways through Smad dephosphorylation. Specifically, the elucidation of the physiological roles of Smad phosphatases-mediated dephosphorylation of Smad1/5/8, and perhaps other R-Smads as well, will provide insights into the important role of BMP/TGF-( signaling in bone growth and development. PUBLIC HEALTH RELEVANCE: The major goal of this research proposal is to investigate the functions of protein phosphatases in bone formation. We have identified three phosphatases as negative regulators of bone morphogenetic proteins (BMP). Our results will be pertinent towards the development of novel therapeutic approaches for the prevention and treatment of human bone diseases.

描述(由申请人提供)：取消细胞对骨形成蛋白(BMPs)和其他转化生长因子超家族成员的反应，这些超家族与人类骨骼疾病有关，如骨质疏松、肺动脉高压和遗传性癌症。我们的长期目标是了解BMP/TGF-1如何调节细胞生长和分化的分子基础，以及BMP信号改变导致人类骨骼疾病生长和分化调控放松的潜在机制。BMPS诱导间充质细胞向成骨细胞分化，促进骨形成。BMP信号转导通路激活的关键事件之一是BMP受体对转录因子Smad1/5/8(Smad1、Smad5和Smad8的统称)的磷酸化。虽然磷酸化的Smad1/5/8直接激活细胞核中的靶基因，但蛋白磷酸酶预计会使磷酸化的Smad1/5/8去磷酸化，从而使BMP信号失活。直到最近，人们一直在追逐的磷酸酶的身份一直是BMP/TGF-(生物学)中尚未回答的主要问题之一。我们发现Smad1/5/8可以被几种磷酸酶去磷酸化。我们对这一建议的短期策略是表征磷酸酶的生化特性，并研究它们在成骨细胞分化过程中调节BMP信号的生物学功能。我们的初步研究(已发表和未发表)导致我们假设Smad磷酸酶在成骨细胞分化过程中阻断或终止BMP信号。因此，研究Smad磷酸酶在骨形成中的生理作用具有重要意义。在这一应用中，我们将重点研究Smad去磷酸化在成骨细胞分化过程中的功能和分子机制。目的1：BMP特异性Smad1/5/8去磷酸化Smad磷酸酶的生化特性。目的2：阐明Smad磷酸酶介导的Smad去磷酸化在BMP信号转导中的作用。目的3：探讨Smad磷酸酶在骨髓间充质干细胞向成骨细胞分化中的作用。 这些实验将为Smad磷酸酶如何通过Smad去磷酸化调控BMP信号通路开辟一个新的研究领域。具体地说，阐明Smad磷酸酶介导的Smad1/5/8以及其他R-Smads的去磷酸化的生理作用，将有助于深入了解BMP/TGF-1信号在骨生长发育中的重要作用。公共卫生相关性：这项研究提案的主要目标是调查蛋白磷酸酶在骨形成中的功能。我们已经鉴定出三种磷酸酶是骨形态发生蛋白(BMP)的负调节因子。我们的研究结果将有助于开发预防和治疗人类骨病的新的治疗方法。