Bone Morphogenic Protein Signaling Pathways in Uterine Biology

子宫生物学中的骨形态发生蛋白信号通路

基本信息

批准号：
8495780
负责人：
MARTIN M. MATZUK
金额：
$ 28.73万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-17 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495780
关键词：
ACVR1 gene ACVR2B gene Ablation Activin Receptor Activins Adverse effects Agonist BMP2 gene BMPR2 gene Binding Binding Proteins Biological Biology Bone Morphogenetic Proteins Cell Nucleus Cells Chemicals Clinical Complex Decidual Cell Reactions Development Dimerization Disease Endometrial Extracellular Domain Family Family member Female Fetal Growth Retardation First Pregnancy Trimester Follistatin Future Gene Expression Genes Genetic Genetic Models Genetic Transcription Goals Gonadal structure Grant Human In Vitro Infertility Institutes Ligands MADH4 gene Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of testis Mammals Mediating Medicine Modeling Mus Muscle Mutation Nature Neonatal New Agents Ovarian Ovary Paper Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Physiology Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy loss Premature Ovarian Failure Process Protein-Serine-Threonine Kinases Proteins Publications Publishing Receptor Serine/Threonine Kinase Recurrence Role Science Signal Pathway Signal Transduction Specificity Staging Stromal Cells Susceptibility Gene Tacrolimus Binding Protein 1A Technology Testing Time Tissues Transforming Growth Factors Uterus Woman activin A bone bone loss bone morphogenetic protein receptors bone morphogenic protein cell type extracellular follow-up implantation in vivo myostatin prevent public health relevance receptor receptor binding reproductive small molecule wasting

项目摘要

DESCRIPTION (provided by applicant): The transforming growth factor 2 (TGF2) superfamily, the largest family of secreted proteins in mammals, includes the bone morphogenetic proteins (BMPs), actives, and myostatin. These ligands signal through a heteromeric complex of type 1 and type 2 serine/threonine kinase receptors. Ligand-induced dimerization of these receptors leads to phosphorylation of receptor-regulated SMAD proteins, which translocate to the nucleus with SMAD4 to regulate gene expression. These signaling pathways have been implicated in many pathophysiologic processes. For example, at the end of the first trimester, activin A levels are elevated in women who will eventually develop preeclampsia, and the BMP/activin/myostatin type 2 receptor, ACVR2A, has been identified as a candidate maternal susceptibility gene for preeclampsia. With the support of this grant that started in 1994, we have generated and analyzed mice with mutations in activin subunits, a ligand binding protein (follistatin), a downstream receptor-binding protein (FKBP12), several SMADs, and multiple BMP/activin/myostatin receptors. The phenotypes of our genetic models range from neonatal lethality to infertility to cancer. These models have been indispensable for deciphering TGF2 superfamily signaling pathways in the gonads and modeling clinical reproductive diseases including infertility, premature ovarian failure, and ovarian and testicular cancer. These HD32067-supported studies have resulted in 43 papers published during the current grant period and 87 publications overall including high impact papers in Nature, Nature Genetics, Nature Medicine, Science, Genes and Development, and Developmental Cell. The overall goals of this R01 renewal will be to follow-up these studies by analyzing the unique and redundant roles of the type 1 and type 2 receptors in BMP signaling in the uterus and identifying new agents for inhibiting and/or mimicking the functions of BMPs, activins and myostatin in uterine, ovarian, muscle, and bone physiology. The Specific Aims of these proposed studies are: 1) Define the BMP receptor pathways in implantation and post- implantation uterine biology, and 2) Identify and synthesize small molecule BMP receptor-specific antagonists and agonists. These proposed studies will allow us to genetically place TGF2 superfamily ligands, receptors, and downstream SMADs into biological pathways in the female reproductive tract, and identify and synthesize compounds for future treatments of human reproductive and non-reproductive diseases.

描述（由申请人提供）：转化生长因子 2 (TGF2) 超家族是哺乳动物中最大的分泌蛋白家族，包括骨形态发生蛋白 (BMP)、活性物质和肌生长抑制素。这些配体通过 1 型和 2 型丝氨酸/苏氨酸激酶受体的异聚复合物发出信号。配体诱导的这些受体的二聚化导致受体调节的 SMAD 蛋白磷酸化，该蛋白与 SMAD4 一起易位到细胞核以调节基因表达。这些信号通路与许多病理生理过程有关。例如，在妊娠早期末，最终会患上子痫前期的女性中激活素 A 水平升高，并且 BMP/激活素/肌生长抑制素 2 型受体 ACVR2A 已被确定为先兆子痫的候选母体易感基因。在 1994 年开始的这项资助的支持下，我们生成并分析了激活素亚基、配体结合蛋白（卵泡抑素）、下游受体结合蛋白（FKBP12）、几种 SMAD 和多种 BMP/激活素/突变的小鼠。肌生长抑制素受体。我们的遗传模型的表型范围从新生儿致死率到不孕症再到癌症。这些模型对于破译性腺中的 TGF2 超家族信号通路以及模拟临床生殖疾病（包括不孕症、卵巢早衰以及卵巢癌和睾丸癌）不可或缺。这些 HD32067 支持的研究在当前资助期内发表了 43 篇论文，总共发表了 87 篇论文，其中包括《自然》、《自然遗传学》、《自然医学》、《科学》、《基因与发育》和《发育细胞》中的高影响力论文。 R01 更新的总体目标是通过分析 1 型和 2 型受体在子宫 BMP 信号传导中的独特和冗余作用，并鉴定用于抑制和/或模拟 BMP 功能的新药物来跟进这些研究。、激活素和肌肉生长抑制素在子宫、卵巢、肌肉和骨骼生理学中的作用。这些拟议研究的具体目标是：1) 定义植入和植入后子宫生物学中的 BMP 受体途径，以及 2) 识别和合成小分子 BMP 受体特异性拮抗剂和激动剂。这些拟议的研究将使我们能够从基因角度将 TGF2 超家族配体、受体和下游 SMAD 置于女性生殖道的生物途径中，并识别和合成用于未来治疗人类生殖和非生殖疾病的化合物。