Mechanisms of Non-Genomic Estrogen Signaling

非基因组雌激素信号传导机制

• 批准号: 7622551
• 负责人: Lisa J Robinson
• 金额: $ 12.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622551
• 关键词: Acute; Agonist; Binding; Biochemical; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Resorption; Cell Line; Cells; Commit; Complex; Cytoskeletal Proteins; Data Reporting; Development; Elderly; Elements; Estradiol; Estrogen Receptors; Estrogen Replacements; Estrogens; Event; Family; Figs - dietary; Fluorescence Microscopy; Goals; Hormones; Human; Immunoprecipitation; Lead; Ligands; Link; Mediating; Mediator of activation protein; Menopause; Mentors; Methods; Modeling; Molecular; Morbidity - disease rate; Nuclear Translocation; Osteoclasts; Osteoporosis; Pathogenesis; Pathology; Postdoctoral Fellow; Postmenopausal Osteoporosis; Process; Program Development; Protein Binding; Proteins; Regulation; Research; Research Personnel; Role; Scaffolding Protein; Selective Estrogen Receptor Modulators; Signal Pathway; Signal Transduction; Signaling Protein; Site-Directed Mutagenesis; Small Interfering RNA; Staging; Stimulus; TNFSF11 gene; Testing; Training; Universities; Work; authority; bone; bone loss; bone mass; career; clinically significant; human BCAR1 protein; insight; malignant breast neoplasm; molecular pathology; non-genomic; professor; programs; protein distribution; protein function; protein protein interaction; receptor; research study; skeletal; therapy design; tumor

DESCRIPTION (provided by applicant): This proposal describes a 5-year program for the development of a career in academic molecular pathology. Dr. Robinson pursued post-doctoral studies on cell signaling at Harvard and pathology training at Duke; she is now a tenure-track Assistant Professor of Pathology at the University of Pittsburgh and fully committed to a research career focused on mechanistic analyses of the regulation of bone and bone marrow cells. Dr. Robinson's mentor for this proposal, a Professor of Pathology at Pittsburgh, is an authority on the regulation of bone resorption and is guiding her new endeavors in the study of osteoclast formation. The long-term goal of the applicant is to understand the interactions between the hematologic and stromal components of the bone marrow and the mechanisms of their reciprocal regulation. The proposed research examines nongenomic estrogen effects on osteoclast formation involving the protein BCAR1. Preliminary studies revealed that estrogen triggers the binding of its receptor to the scaffolding protein BCAR1. This association is sensitive to receptor agonists and modulators, as well as to RANKL, the major stimulus for osteoclast differentiation. RANKL stimulated osteoclast differentiation is inhibited by estrogen through acute effects on RANKL signal transduction. When BCAR1 expression is inhibited, however, estrogen effects on RANKL signaling are abrogated. In addition, BCAR1 interacts with RANKL signaling in the absence of estrogen, and in its absence, osteoclast formation is inhibited. These results indicate that a complex network of interactions links BCAR1 to both estrogen and RANKL. Proposed studies test the hypothesis that BCAR1 mediates nongenomic estrogen effects in pre-osteoclasts by forming a complex with the estrogen receptor that interacts with RANKL signaling mechanisms. The specific aims are to: define components of the ER-BCAR1 complex and their regulation by estrogen and RANKL, and identify the molecular mechanisms by which BCAR1, and estrogen through ER-BCAR1, modulate RANKL signaling to regulate osteoclast formation. Clinical significance: these studies will define the molecular mechanisms by which estrogen inhibits bone resorption (anti-osteoporosis effect). They focus on BCAR1, a protein implicated in estrogen effects on breast cancer. Understanding the mechanisms by which this protein functions in bone is important for the design of therapies that treat osteoporosis without exacerbating hormone dependent tumor formation or progression.

描述（由申请人提供）：该提案描述了一项为期5年的学术分子病理事业的计划。鲁滨逊博士在哈佛大学和杜克大学病理学培训上进行了博士后研究；她现在是匹兹堡大学的终身训练助理教授，并完全致力于研究骨骼和骨髓细胞调节机械分析的研究生涯。匹兹堡病理学教授罗宾逊博士的这一提议的导师是对骨吸收调节的权威，并正在指导她在骨细胞形成的研究中指导她的新努力。申请人的长期目标是了解骨髓的血液学和基质成分之间的相互作用及其相互调节的机制。拟议的研究研究了非元素雌激素对涉及蛋白BCAR1的破骨细胞形成的影响。初步研究表明，雌激素会触发其受体与脚手架蛋白BCAR1的结合。该关联对受体激动剂和调节剂以及RANKL敏感，RANKL是破骨细胞分化的主要刺激。雌激素通过对RANKL信号转导的急性影响抑制了RANKL刺激的破骨细胞分化。然而，当抑制BCAR1表达时，雌激素对RANKL信号的影响被废除。另外，在不存在雌激素的情况下，BCAR1与RANKL信号传导相互作用，在没有雌激素的情况下，抑制破骨细胞的形成。这些结果表明，复杂的相互作用网络将BCAR1连接到雌激素和RANKL。拟议的研究检验了BCAR1通过与雌激素受体形成复合物与RANKL信号传导机制相互作用的复合物，从而介导了骨前细胞中的非根原质雌激素作用的假设。具体目的是：定义ER-BCAR1复合物的组成部分及其对雌激素和RANKL的调节，并确定通过ER-BCAR1通过ER-BCAR1通过ER-BCAR1进行的分子机制，调节RANKL信号传导以调节骨细胞的形成。临床意义：这些研究将定义雌激素抑制骨吸收的分子机制（抗骨质疏松作用）。它们专注于BCAR1，这是一种涉及雌激素对乳腺癌的影响的蛋白质。了解该蛋白在骨骼中起作用的机制对于设计治疗骨质疏松症的疗法至关重要，而不会加剧激素依赖性肿瘤的形成或进展。