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: 7526490
• 负责人: XIN-HUA FENG
• 金额: $ 29.22万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7526490
• 关键词: Area; Biochemical; Biological Process; Biology; Bone Diseases; Bone Growth; Bone Marrow; Bone Morphogenetic Proteins; Cell Nucleus; Cell physiology; Cells; Complex; Data; Development; Differentiation and Growth; Event; Gene Expression; Gene Targeting; Genomics; Goals; Growth and Development function; Human; Investigation; Knock-out; Lead; Malignant Neoplasms; Mediating; Mesenchymal Differentiation; Mesenchymal Stem Cells; Molecular; Mus; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Prevention approach; Property; Protein Dephosphorylation; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Public Health; 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 therapeutics; nucleocytoplasmic transport; 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）：细胞对骨形态发生蛋白 (BMP) 和 TGF-( 超家族其他成员的反应的取消与骨质疏松症、肺动脉高压和遗传性癌症等人类骨骼疾病有关。我们的长期目标是了解BMP/TGF-( 调节细胞生长和分化的分子基础，以及 BMP 信号传导的改变导致人类骨疾病中生长和分化控制失调的潜在机制。BMP 诱导分化BMP 信号转导通路激活中最关键的事件之一是 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 Smad1/5/8 去磷酸化，从而失活BMP 信号传导。直到最近，长期以来备受追捧的磷酸酶的身份一直是 BMP/TGF-( 生物学中未解答的主要问题之一。我们发现 Smad1/5/8 可以被几种磷酸酶去磷酸化。我们的短期策略该提案旨在表征磷酸酶的生化特性并研究其在成骨细胞分化过程中 BMP 信号传导调节中的生物学功能。我们的初步研究（已发表和未发表）使我们推测 Smad。因此，研究 Smad 磷酸酶在成骨细胞分化过程中的生理作用具有重要意义。在本应用中，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。提出了三个具体目标： 目标 1：用于 BMP 特异性 Smad1/5/8 去磷酸化的 Smad 磷酸酶的生化表征。目标 2：阐明 Smad 磷酸酶介导的 Smad 去磷酸化在 BMP 信号传导中的功能。目标 3：研究 Smad 磷酸酶在间充质干细胞向成骨细胞分化中的作用。 拟议的实验将开启一个关于 Smad 磷酸酶如何通过 Smad 去磷酸化调节 BMP 信号通路的新研究领域。具体来说，阐明 Smad 磷酸酶介导的 Smad1/5/8 以及其他 R-Smad 去磷酸化的生理作用，将有助于深入了解 BMP/TGF-( 信号传导在骨骼生长和发育中的重要作用。公共健康相关性：本研究计划的主要目标是研究蛋白磷酸酶在骨形成中的功能，我们已经确定了三种磷酸酶作为骨形态发生蛋白的负调节剂。 （BMP）。我们的结果将有助于开发预防和治疗人类骨骼疾病的新治疗方法。