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Distinguishing plasminogen-dependent and plasminogen-independent roles of the plasminogen receptor, Plg-RKT

区分纤溶酶原受体 Plg-RKT 的纤溶酶原依赖性和纤溶酶原非依赖性作用

基本信息

批准号：
10219891
负责人：
Lindsey A Miles
金额：
$ 22.19万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-19 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219891
关键词：
Address Affect Agonist Amino Acids Basic Amino Acids Binding Binding Proteins Biological Biological Assay Birth Breast Feeding Breast Fibrocystic Disease C-terminal Cardiovascular Diseases Cardiovascular system Cell Survival Cell surface Cells Cessation of life Child Competence Data Defect Development Diabetes Mellitus Disease Duct (organ) structure Eczema Elements Embryo Epithelial Epithelial Cell Proliferation Epithelial Cells Exploratory/Developmental Grant Face Fatty acid glycerol esters Female Fibrin Fibrinolysis Fibrosis Future Gland Goals Growth Factor Health Benefit Hormones Human Human Milk Hyperlipidemia Hypertension Impairment Infant Integral Membrane Protein Invaded Kidney Knowledge Laboratories Lacrimal gland structure Lactation Lead Ligands Literature Lobular Lysine Malignant Neoplasms Mammary Neoplasms Mammary gland Morbidity - disease rate Morphogenesis Mothers Mus Nulliparity Obesity Oranges Organ Pathologic Pathologic Processes Pattern Peptide Hydrolases Performance Physiological Processes Plasminogen Play Population Pregnancy Process Prostate Proteomics Puberty Public Health Regulation Research Risk Risk Factors Role Salivary Glands Structural Models System Tissues Transgenes Visceral Weaning Woman base cardiovascular disorder risk cell type cognitive development experimental study gastrointestinal infection hormone receptor-positive improved insight lactogenesis malignant breast neoplasm mammary mammary gland development milk secretion mortality novel obesity in children offspring plasminogen receptor pregnant premature response response to injury triple-negative invasive breast carcinoma

项目摘要

Project Summary/Abstract Competent lactation is essential for mammalian survival and the sustenance of many human populations. Breastfeeding is mutually beneficial for both mothers and infants. Mammary development to achieve lactational competence is regulated by hormones, growth factors and proteinases. However, the identity of these elements and how they interact to effect mammary development are not fully understood. Previous studies have documented a partial lactational defect in plasminogen deficient mice. A critical gap in knowledge is how components of the plasminogen activation system regulate lactation. The plasminogen receptor, Plg-RKT, is a novel integral membrane protein that binds plasminogen and promotes plasminogen activation on cell surfaces. The broad, long-term goal of our laboratory is to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes. This proposal is based on our data demonstrating complete absence of lactational competence, resulting in death of all offspring of Plg-RKT deficient female mice. In addition to a defect in fibrinolysis, Plg-RKT deficiency also leads to severe defects in mammary gland development that do not take place in plasminogen deficient mice. We propose to extend these discoveries toward a new direction by performing exploratory/developmental studies. The objective of this proposal is to elucidate plasminogen- independent mechanisms by which Plg-RKT regulates lactation. The central hypothesis to be addressed is that Plg-RKT is expressed by specific mammary cell types that function to regulate lactational development via both plasminogen-dependent and plasminogen-independent mechanisms. To address our hypothesis, our specific aims are: 1) to distinguish plasminogen-independent and -dependent functions of Plg-RKT in lactational development; and 2) to identify ligands, in addition to plasminogen, that interact with Plg-RKT. Studies will be carried out in Plg-RKT-/- mice and in mice harboring a PLGRKT transgene incapable of binding plasminogen. We expect that accomplishment of our specific aims will provide fundamental insights into new mechanisms by which lactational development is regulated. The results obtained may also lead in the future to understanding biological mechanisms through which suboptimal lactation affects the risk for cardiovascular disease and cancer in women. These studies also have high relevance for understanding the basis of mammary fibrosis, a key process in fibrocystic breast disease. New insights resulting from these studies are also expected to have a major impact on our understanding of a broad array of pathological and physiological processes in organs that undergo post-embryonic morphogenesis in response to injury, including kidney and prostate. Performance of the proposed experiments is expected to suggest new targets and cell-based assays that potentially can be used to screen for agonists that may promote Plg-RKT function and/or expression to promote lactation, to treat mammary fibrosis, and to treat diseases involving dysregulated post-embryonic morphogenesis.

项目总结/摘要哺乳期的哺乳对于哺乳动物的生存和许多人类的生计至关重要。母乳喂养对母亲和婴儿都有好处。哺乳期乳房发育感受态受激素、生长因子和蛋白酶调节。然而，这些元素的特性以及它们如何相互作用以影响乳房发育尚未完全了解。先前的研究记录了纤溶酶原缺陷小鼠的部分泌乳缺陷。一个关键的知识缺口是如何纤溶酶原激活系统的组分调节泌乳。纤溶酶原受体Plg-RKT是一种结合纤溶酶原并促进细胞表面纤溶酶原活化的新型整合膜蛋白。我们实验室广泛的长期目标是了解Plg-RKT调节的机制。生理和病理过程。这一建议是基于我们的数据表明完全没有哺乳能力，导致Plg-RKT缺陷雌性小鼠的所有后代死亡。除了一个缺陷在纤维蛋白溶解中，Plg-RKT缺乏也导致乳腺发育的严重缺陷，在纤溶酶原缺陷小鼠中。我们建议将这些发现扩展到一个新的方向，进行探索性/发展性研究。本提案的目的是阐明纤溶酶原- Plg-RKT调节泌乳的独立机制。要解决的中心假设是， Plg-RKT由特定的乳腺细胞类型表达，其功能是通过以下两种途径调节哺乳发育：纤溶酶原依赖性和纤溶酶原非依赖性机制。为了解决我们的假设，我们的具体目的是：1）区分Plg-RKT在哺乳期的纤溶酶原非依赖性和依赖性功能，开发;和2）鉴定除纤溶酶原外与Plg-RKT相互作用的配体。研究将在Plg-RKT-/-小鼠和携带不能结合的PLGRKT转基因的小鼠中进行。纤溶酶原我们期望，实现我们的具体目标将为新的哺乳期发育的调节机制。所取得的成果也可能导致在未来，了解次优泌乳影响心血管疾病风险的生物学机制女性的疾病和癌症。这些研究对于理解乳腺癌的基础也具有高度的相关性。纤维化，纤维囊性乳腺疾病的关键过程。这些研究也有望产生新的见解对我们理解一系列广泛的病理和生理过程产生重大影响，对损伤作出反应而经历胚胎后形态发生的器官，包括肾脏和前列腺。预期所提出的实验的性能将提出新的靶点和基于细胞的测定，潜在地可用于筛选可促进Plg-RKT功能和/或表达以促进哺乳，治疗乳腺纤维化，和治疗涉及胚胎后发育失调的疾病形态发生