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：
7213231
负责人：
MARTIN M. MATZUK
金额：
$ 32.11万
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 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213231
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）：转化的生长因子β（TGFBETA）超家族是哺乳动物中最大的分泌蛋白质家族。该家族包括刺激，抑制剂，TGFBETA，骨形态发生蛋白（BMP）和生长分化因子（GDFS）。这些配体通过跨膜I型和II型丝氨酸/苏氨酸激酶受体的寡聚复合物进行信号。配体诱导的这些受体的异二聚化导致受体调节的SMAD蛋白的磷酸化，这些蛋白具有常见的SMAD4蛋白并调节基因表达。在这些信号传导途径中具有突变的小鼠和人类的表征揭示了该家族起作用的发育和生理过程的多样性。通过该赠款的支持，我的实验室在激活素亚基，激活蛋白结合蛋白（Follistatin），激活素受体II型，下游受体结合蛋白（FKBP 12）和SMADS中产生并分析了小鼠。我们最近表明，卵泡蛋白的颗粒细胞消融小鼠是女性过早卵巢衰竭的模型。这些基因敲除小鼠在定义体内基因功能方面的实用性是无与伦比的，这些强大的遗传模型对于研究发展和繁殖是必不可少的。此R01更新的总体假设是，我们将能够使用可用且新创建的卵巢特异性基因敲除小鼠模型在卵巢中解剖TGFBETA信号通路。这些研究将使我们能够将配体，受体和下游SMAD蛋白置于单个细胞类型的生物途径（即卵巢的颗粒细胞）中。拟议的研究的具体目的如下：1）产生转基因模型来定义激活素的内部作用； 2）剖析卵巢中II型，BMP受体II型和BMP受体I型信号通路； 3）研究卵巢生理学中下游SMAD蛋白的相互关系。这些转基因小鼠的产生和表征将定义卵巢中必不可少的TGFA超家族信号传导成分和途径，并将继续成为人类生殖疾病的重要模型，包括不育症，早产卵巢衰竭，多卵巢卵巢卵巢综合征和卵巢癌。