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

• 批准号: 8150354
• 负责人: MARTIN M. MATZUK
• 金额: $ 28.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/8150354
• 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

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. PUBLIC HEALTH RELEVANCE: The transforming growth factor 2 (TGF2) superfamily is the largest family of secreted proteins in mammals, and TGF2 signaling pathways have been implicated in a diversity of developmental and pathophysiological processes including preeclampsia. Over the last 19 years, we have used multiple in vivo and in vitro approaches to dissect the essential and redundant roles of these signaling pathways. The objectives of this R01 renewal are to mechanistically define the unique and redundant roles of the bone morphogenetic protein (BMP) type 1 and type 2 receptors during implantation and post-implantation and to identify new drugs for inhibiting or mimicking the functions of BMPs, activins, and myostatin for treatments of clinically important reproductive and non-reproductive diseases.

描述（由申请人提供）：哺乳动物中最大的分泌蛋白质家族的转化生长因子2（TGF2）包括骨形态发生蛋白（BMP），活性物和肌生抑素。这些配体通过1型和2型丝氨酸/苏氨酸激酶受体的异质体复合物发出信号。这些受体的配体诱导的二聚化导致受体调节的Smad蛋白的磷酸化，后者用Smad4转移到细胞核中以调节基因表达。这些信号通路已与许多病理生理过程有关。例如，在头三个月结束时，最终将发展先兆子痫的女性中，激活素A水平升高，而BMP/Activin/Myostatin 2型受体ACVR2A已被鉴定为候选孕妇对子痫的候选母体易感基因。在始于1994年的这笔赠款的支持下，我们已经在激活素亚基中产生了和分析了小鼠，该突变是一种配体结合蛋白（Follistatin），下游受体结合蛋白（FKBP12），几种SMADS和多个BMP/激活素/肌蛋白蛋白受体。我们遗传模型的表型从新生儿致死性到不育，再到癌症。这些模型对于在性腺中解解TGF2超家族信号通路和对临床生殖疾病（包括不育，早产卵巢衰竭以及卵巢癌和卵巢癌）进行建模是必不可少的。这些HD32067支持的研究导致了当前赠款期间发表的43篇论文，总体上有87个出版物，包括自然，自然遗传学，自然医学，科学，基因和发展以及发育细胞的高影响力论文。该R01更新的总体目标将是通过分析子宫中BMP信号中1型和2型受体的独特和冗余作用，并鉴定新的药物在子宫，卵巢，卵巢，肌肉，肌肉，肌肉学中抑制和/或模仿BMPS，激活素和肌蛋白酶的功能。这些提出的研究的具体目的是：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。这些提出的研究将使我们能够将TGF2超家族，受体和下游SMAD置于女性生殖道的生物途径中，并鉴定并合成化合物，以使未来的人类生殖和非促成疾病治疗。 公共卫生相关性：转化生长因子2（TGF2）超家族是哺乳动物中最大的分泌蛋白质家族，TGF2信号传导途径与包括先兆子痫在内的发育和病理生理过程的多样性有关。在过去的19年中，我们使用了多种体内和体外方法来剖析这些信号通路的必要和冗余作用。该R01更新的目标是在植入和植入后植入期间机械定义骨形态发生蛋白（BMP）1型和2型受体的独特和冗余作用，并识别新药，以抑制或模仿BMPS，激活素，肌抑制素的功能，以及肌抑制蛋白的功能，以及肌抑制症的convertive脚和contuctive乱的多次繁殖。