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

妊娠相关血浆蛋白 A 替代底物的鉴定

• 批准号: 7515599
• 负责人: James Lawrence
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF WISCONSIN STEVENS POINT
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7515599
• 关键词: Age; Aging; Atherosclerosis; Binding; Biochemical Pathway; Biological; Biological Assay; Biological Availability; Biological Models; Bone remodeling; Cell surface; Cleaved cell; Down Syndrome; Endopeptidases; Fetal Development; First Pregnancy Trimester; Gel; Goals; Growth Factor; High Pressure Liquid Chromatography; Histocompatibility Testing; Human; In Vitro; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor Receptor; Insulin-Like Growth-Factor-Binding Proteins; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Link; Liquid Chromatography; Malignant Neoplasms; Metalloproteases; Molecular Weight; Mus; Pattern; Peptide Fragments; Peptide Hydrolases; Peptides; Phase; Plasma; Pregnancy; Pregnancy-Associated Plasma Protein-A; Protein Biochemistry; Proteins; Proteolysis; Proteomics; Public Health; Purpose; Reporting; Research; Research Personnel; Role; Sampling; Screening procedure; Serum; Signal Transduction; Somatomedins; Staining method; Stains; Students; System; Techniques; Technology; Time; Tissues; Two-Dimensional Gel Electrophoresis; Variant; Wild Type Mouse; Wound Healing; acute coronary syndrome; base; career; cyanine dye 5; gel electrophoresis; human IGFBP2 protein; human disease; mouse model; novel; polypeptide; programs; protein expression; tandem mass spectrometry; tool; two-dimensional

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.

描述（由申请人提供）：妊娠相关血浆蛋白-A（PAPP-A）于1974年被鉴定为正常人妊娠血清中的四种蛋白质标志物之一。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。这种切割导致IGFs从IGFBP-4隔离中释放，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剂。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PAPP-A在过去已经被积极地研究，但很少有证据直接涉及PAPP-A或其在IGFs以外的生物系统中的蛋白水解活性。本申请的目的是使用开放式蛋白质组学工具探测来自小鼠PAPP-A无效和野生型组织的样品，以确定PAPP-A是否切割生物系统中除IGFBP-4以外的蛋白质。具体而言，我们将使用二维凝胶电泳和液相色谱法来比较PAPP-A无效组织的蛋白表达模式与野生型组织的蛋白表达模式。发现的任何蛋白质表达差异可能是PAPP-A蛋白水解活性的直接或间接结果。将鉴定表达改变的蛋白质。从这些蛋白质的鉴定中获得的信息将提示PAPP-A的新生物学作用，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传导的重要调节剂。PAPP-A与多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，然而缺乏PAPP-A在这些系统中蛋白水解活性的直接证据。本申请的目的是研究和发现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。