PLATELETS IN IMMUNE GLOMERULAR INJURY

免疫性肾小球损伤中的血小板

• 批准号: 2133898
• 负责人: Richard Joseph Johnson
• 金额: $ 6.59万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1997-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2133898
• 关键词: autocrine; cell cycle; gene expression; glomerulonephritis; immunocytochemistry; in situ hybridization; inflammation; interleukin 1; mesangium; northern blottings; platelet derived growth factor; platelets; tissue /cell culture; autocrine; cell cycle; gene expression; glomerulonephritis; immunocytochemistry; in situ hybridization; inflammation; interleukin 1; mesangium; northern blottings; platelet derived growth factor; platelets; tissue /cell culture

Platelets (PLTs) are important inflammatory effector cells in glomerulonephritis (GN). Our hypothesis is that PLTs have an important role in mediating glomerular cell proliferation in GN via mechanisms involving release by the PLT of growth factors, as well as stimulation of intrinsic glomerular cells to produce their own (i.e., autocrine) growth factors. In Specific Aim #1 we will follow up on our observation that PLT- mediated mesangial cell (MC) proliferation in an immune model of GN involves an upregulation of MC to produce the autocrine growth factor, platelet-derived growth factor (PDGF), and PDGF receptor (PDGF-R). Specifically, we will determine if PLTs mediate glomerular cell proliferation in other nonimmune models of proliferative GN (such as induced by toxins or hemodynamic mechanisms) and if this involves stimulation of MC to upregulate PDGF and PDGF-R. Studies will include localization of PDGF and PDGF-R by immunocytochemistry, quantitation of PDGF and PDGF-R in isolated glomeruli, and measurements of glomerular PDGF and PDGF-R mRNA by Northern analysis with localization by in situ hybridization. In Specific Aim #2, we will determine if PLT-mediated MC proliferation is associated with upregulation by the MC of another autocrine growth factor, interleukin I (IL-1). Studies will be similar to Specific Aim #1 and will involve both localization and quantitation of IL-1 and IL-1 receptor mRNA and protein in an immune model of mesangial proliferative GN. In Specific Aim #3, we will determine the role of PDGF in mediating MC proliferation in a PLT-mediated model of mesangial proliferation GN by attempting to block in vivo PDGF with a specific anti- PDGF antibody. Finally, in Specific Aim #4, we will pursue our observation that PLTs mediate an upregulation of PDGF-R on MC in GN by determining what PLT factor(s) modulate MC expression of PDGF-R in cell culture. These studies will confirm the importance of the PLT in proliferative GN and will define the mechanisms involved, specifically the importance of PLTs in mediating the MC to produce autocrine growth factors, and the role of PDGF in glomerular disease.

血小板（PLT）是重要的炎症效应细胞 肾小球肾炎（GN）。 我们的假设是PLT具有重要的 通过机制介导GN中肾小球细胞增殖的作用 涉及生长因子的PLT释放，以及刺激 固有的肾小球细胞以产生自己的（即自分泌）生长 因素。 在特定的目标＃1中，我们将跟进我们的观察结果 GN免疫模型中介导的介膜细胞（MC）增殖 涉及MC的上调以产生自分泌生长因子， 血小板衍生的生长因子（PDGF）和PDGF受体（PDGF-R）。 具体而言，我们将确定PLT是否介导肾小球细胞 在其他非免疫模型的增殖模型中的增殖（例如 由毒素或血液动力学机制诱导），如果这涉及 刺激MC上调PDGF和PDGF-R。 研究将包括 通过免疫细胞化学定位PDGF和PDGF-R的定位，定量 孤立肾小球中的PDGF和PDGF-R，以及肾小球PDGF的测量 通过北部分析和原位定位的PDGF-R mRNA 杂交。 在特定的目标＃2中，我们将确定PLT介导的MC是否 增殖与MC的上调有关 自分泌生长因子，白介素I（IL-1）。 研究将与 特定的目标＃1，将涉及IL-1的本地化和定量 肾小球免疫模型中的IL-1受体mRNA和蛋白质 增生性GN。 在特定的目标＃3中，我们将确定PDGF的作用 在介导MC介导的介导模型中的MC增殖中 通过尝试阻止特定抗 - PDGF抗体。 最后，在特定的目标＃4中，我们将进行观察 通过确定什么 PLT因子（S）调节细胞培养中PDGF-R的MC表达。 这些 研究将证实PLT在增殖性GN中的重要性，并将 定义涉及的机制，特别是PLT在 介导MC产生自分泌生长因子和PDGF的作用 在肾小球疾病中。