Functional Analysis of Activins During Development

发育过程中激活蛋白的功能分析

基本信息

批准号：
7409195
负责人：
MARTIN M. MATZUK
金额：
$ 31.47万
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 2010-09-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7409195
关键词：
ACVR2 gene ACVR2B gene Ablation Activins Adult Apoptosis Appendix BMP4 BMP7 gene BMPR2 gene Binding Binding Proteins Biochemical Biological Birth Bone Morphogenetic Proteins Cell Nucleus Complex Data Defect Development Differentiation and Growth Disease Embryo Exencephalies Family Family member Female Fertility Follicle Stimulating Hormone Follistatin GDF9 gene Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Models Grant Growth Growth Differentiation Factor 9 Growth Factor Heart failure Heterodimerization Heterozygote Homozygote Hour Human In Vitro Individual Infertility Knock-out Knockout Mice Laboratories Left Life Ligands Liver MADH2 gene MADH3 gene MADH4 gene MADH6 gene MADH7 gene Malignant neoplasm of ovary Mammals Manuscripts Mediating Meiosis Modeling Mus Muscle Mutant Strains Mice Mutate Mutation Newborn Infant Oocytes Ovarian Ovarian Granulosa Cell Ovary Pathway interactions Phenotype Phosphorylation Physiological Processes Physiology Play Polycystic Ovary Syndrome Premature Ovarian Failure Proteins Receptor Activation Receptor Serine/Threonine Kinase Reproduction Reproductive Physiology Research Personnel Role Secondary to Signal Pathway Signal Transduction Signaling Protein Skin Staging Structure of primordial sex cell System Tacrolimus Binding Proteins Testing Tissues Transforming Growth Factor beta Transforming Growth Factors Transgenic Mice Transgenic Model Type II Activin Receptors Ventricular Woman activin A activin B base body system bone morphogenetic protein receptor type I bone morphogenetic protein receptor type II cell growth cell type craniofacial dosage extracellular folliculogenesis gene function granulosa cell in vivo inhibin intraovarian male mouse model postnatal programs receptor receptor binding recombinase reproductive response tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The transforming growth factor beta (TGFbeta) superfamily is the largest family of secreted proteins in mammals. This family includes the activins, inhibins, TGFbetas, bone morphogenetic proteins (BMPs), and growth differentiation factors (GDFs). These ligands signal through an oligomeric complex of transmembrane type I and type II serine/threonine kinase receptors. Ligand-induced heterodimerization of these receptors leads to phosphorylation of receptor-regulated SMAD proteins, which translocate to the nucleus with the common SMAD4 protein and regulate gene expression. The characterization of mice and humans with mutations in these signaling pathways has revealed the diversity of developmental and physiological processes in which this family functions. Through the support of this grant, my laboratory has generated and analyzed mice with mutations in activin subunits, an activin binding protein (follistatin), activin receptor type II, a downstream receptor binding protein (FKBP 12), and SMADS. We have recently shown that mice with granulosa cell ablation of follistatin are a model for premature ovarian failure in women. The utility of these knockout mice in defining gene function in vivo is unparalleled, and these powerful genetic models have been indispensable for investigating development and reproduction. The overall hypothesis of this R01 renewal is that we will be able to dissect the TGFbeta signaling pathways in the ovary using available and newly-created ovary-specific knockout mouse models. These studies will allow us to place ligands, receptors, and downstream SMAD proteins into biological pathways in a single cell type (i.e., The granulosa cells of the ovary). The Specific Aims of the proposed studies are as follows: 1) Produce transgenic models to define the intraovarian roles of activins; 2) Dissect the activin receptor type II, BMP receptor type II, and BMP receptor type I signaling pathways in the ovary; and 3) Study the interrelationships of the downstream SMAD proteins in ovarian physiology. Generation and characterization of these transgenic mice will define essential and interacting TGFa superfamily signaling components and pathways in the ovary and will continue to be important models for human reproductive diseases including infertility, premature ovarian failure, polycystic ovary syndrome, and ovarian cancer.

描述（由申请人提供）：转化生长因子β（TGFbeta）超家族是哺乳动物中最大的分泌蛋白家族。该家族包括激活素、抑制素、TGFbeta、骨形态发生蛋白 (BMP) 和生长分化因子 (GDF)。这些配体通过 I 型和 II 型跨膜丝氨酸/苏氨酸激酶受体的寡聚复合物发出信号。配体诱导的这些受体的异二聚化导致受体调节的 SMAD 蛋白磷酸化，该蛋白与常见的 SMAD4 蛋白一起易位到细胞核并调节基因表达。这些信号通路突变的小鼠和人类的特征揭示了该家族功能的发育和生理过程的多样性。通过这笔资助的支持，我的实验室已经生成并分析了激活素亚基、激活素结合蛋白（卵泡抑素）、激活素受体 II 型、下游受体结合蛋白 (FKBP 12) 和 SMADS 突变的小鼠。我们最近发现，颗粒细胞去除卵泡抑素的小鼠是女性卵巢早衰的模型。这些基因敲除小鼠在体内定义基因功能方面的效用是无与伦比的，这些强大的遗传模型对于研究发育和繁殖是不可或缺的。 R01 更新的总体假设是，我们将能够使用现有的和新创建的卵巢特异性敲除小鼠模型来剖析卵巢中的 TGFbeta 信号通路。这些研究将使我们能够将配体、受体和下游 SMAD 蛋白放入单一细胞类型（即卵巢的颗粒细胞）的生物途径中。拟议研究的具体目标如下： 1）产生转基因模型来定义激活素的卵巢内作用； 2）剖析卵巢中的激活素受体II型、BMP受体II型、BMP受体I型信号通路； 3) 研究下游SMAD蛋白在卵巢生理学中的相互关系。这些转基因小鼠的产生和表征将定义卵巢中重要且相互作用的 TGFα 超家族信号传导成分和途径，并将继续成为人类生殖疾病（包括不孕症、卵巢早衰、多囊卵巢综合征和卵巢癌）的重要模型。