Identification of Alternative Substrates of Pregnancy-Associated Plasma Protein-A

描述（由申请人提供）：妊娠相关血浆蛋白a（妊娠相关血浆蛋白a）于1974年被确定为正常人类妊娠血清中的四种蛋白标记物之一。PAPP-A是一种金属蛋白酶，可将胰岛素样生长因子结合蛋白-4 （IGFBP-4）切割成2个片段。这种分裂导致IGFBP-4隔离释放IGFs，并允许胰岛素样生长因子（IGFs）与细胞表面IGF受体结合。因此，PAPP-A是IGF生物利用度的重要调节因子。自这一发现以来，PAPP-A已涉及多种生物系统，包括胎儿发育、骨重塑、伤口愈合、动脉粥样硬化、急性冠状动脉综合征、衰老和癌症。尽管过去对PAPP-A的研究非常积极，但很少有证据直接表明PAPP-A或其在除IGFs以外的生物系统中的蛋白水解活性。本应用程序的目的是使用开放式蛋白质组学工具探测来自小鼠PAPP-A零型和野生型组织的样品，以确定PAPP-A是否在生物系统中切割除IGFBP-4以外的蛋白质。具体来说，我们将使用二维凝胶电泳和液相色谱来比较PAPP-A零组织与野生型组织的蛋白质表达模式。发现的任何蛋白表达差异都可能是PAPP-A蛋白水解活性的直接或间接结果。改变表达的蛋白质将被识别。从这些蛋白质的鉴定中获得的信息将提示PAPP-A的新的生物学作用，并可能导致PAPP-A与人类疾病之间的直接联系。公共卫生相关性：妊娠相关血浆蛋白a （PAPP-A）是胰岛素样生长因子信号的重要调节剂。PAPP-A与几种人类生物系统有关，包括动脉粥样硬化、急性冠状动脉综合征、衰老和癌症，但缺乏直接证据表明PAPP-A在这些系统中具有蛋白水解活性。本申请的目的是调查和发现PAPP-A蛋白水解活性与已知或新的生物系统之间的直接联系。

DESCRIPTION (provided by applicant): Pregnancy Associated Plasma Protein-A (PAPP-A) was identified in 1974 as one of four protein markers in normal human pregnancy serum. PAPP-A is a metalloprotease that cleaves Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) into 2 fragments. This cleavage causes the release of IGFs from IGFBP-4 sequestration and allows the Insulinlike Growth Factors (IGFs) to bind to the cell surface IGF receptor. Thus PAPP-A is an important regulator of IGF bioavailability. Since this discovery, PAPP-A has been implicated in a variety of biological systems including fetal development, bone remodeling, wound healing, atherosclerosis, acute coronary syndrome, aging and cancer. In spite of the fact that PAPP-A has been aggressively studied in the past, there is very little evidence to directly implicate PAPP-A or it's proteolytic activity in biological systems other than the IGFs. The purpose of this application is to probe samples from mouse PAPP-A null and wild-type tissue using open ended proteomic tools in order to determine if PAPP-A cleaves proteins other than IGFBP-4 in biological systems. Specifically we will use two dimensional gel electrophoresis and liquid chromatography to compare the protein expression pattern of the PAPP-A null tissue against the protein expression pattern of the wild-type tissue. Any protein expression differences discovered are likely to be the direct or indirect result of PAPP-A proteolytic activity. The proteins with altered expression will be identified. The information gained from the identification of these proteins will suggest novel biological roles for PAPP-A and may lead to the direct link between PAPP-A and human diseases. PUBLIC HEALTH RELEVANCE: Pregnancy-Associated Plasma Protein-A (PAPP-A) is an important modulator of Insulin- like Growth Factor signaling. PAPP-A has been implicated in several human biological systems, including atherosclerosis, acute coronary syndrome, aging and cancer, however direct evidence of PAPP-A proteolytic activity in these systems is lacking. This goal of this application is to investigate and discover a direct link between PAPP-A proteolytic activity and known or novel biological systems.