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

项目摘要/摘要 良好的哺乳对于哺乳动物的生存和许多人类种群的生存是必不可少的。 母乳喂养对母亲和婴儿都是有益的。乳房发育实现哺乳期 能力受激素、生长因子和蛋白酶的调节。然而，这些元素的身份 它们是如何相互作用影响乳腺发育的，目前还不完全清楚。之前的研究已经 记录了纤溶酶原缺陷小鼠的部分哺乳缺陷。知识上的一个关键差距是如何 纤溶酶原激活系统的组成部分调节哺乳。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激活的新型完整膜蛋白。 我们实验室广泛而长期的目标是了解PLG-RKT调节机制。 生理和病理过程。这项建议是基于我们的数据显示完全没有 哺乳能力，导致PLG-RKT缺陷雌性小鼠的所有后代死亡。除了缺陷之外 在纤溶过程中，plg-rkt缺乏也会导致严重的乳腺发育缺陷。 放入纤溶酶原缺陷小鼠体内。我们建议通过以下方式将这些发现扩展到一个新的方向 进行探索性/发展性研究。这项建议的目的是阐明纤溶酶原- PLG-RKT调节哺乳的独立机制。需要解决的中心假设是 PLG-RKT由特定类型的乳腺细胞表达，这些细胞通过两种途径调节哺乳发育 纤溶酶原依赖和非纤溶酶原依赖机制。为了解决我们的假设，我们的特定 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)确定除纤溶酶原外，与PLG-RKT相互作用的配体。 研究将在PLG-RKT-/-小鼠和携带PLGRKT转基因而不能结合的小鼠身上进行 纤溶酶原。我们期待我们特定目标的实现将为我们提供对新的 调节哺乳期发育的机制。所获得的结果也可能在未来导致 了解哺乳不佳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的基础也具有很高的相关性 纤维化，纤维囊性乳腺疾病的关键过程。这些研究也有望带来新的见解。 对我们理解一系列广泛的病理和生理过程产生重大影响 胚胎后发生形态发生反应的器官，包括肾脏和前列腺。 拟议实验的性能预计将提出新的靶点和基于细胞的分析， 潜在地可用于筛选可能促进PLG-RKT功能和/或表达以促进 哺乳，治疗乳腺纤维化，以及涉及胚胎后调节失调的疾病 形态发生。

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.