GROWTH FACTORS AND MESANGIAL MATRIX METABOLISM

肾小球基底膜与系膜基质 代表高度专门化的细胞外基质(ECM)。 由固有的肾小球细胞合成，这是一种专门的 据推测，Matrix经历了正常的分解代谢周转。在.期间 各种病理状态，有可能是不受监管的 肾小球ECM分解代谢可导致结构损伤 这些关键要素。此外，与以下疾病相关的障碍 矩阵积累增加的部分原因可能是干扰 正常的基质分解代谢过程。获得的证据 从其他ECM系统，如骨，已经证明 多肽生长因子在细胞内发挥重要作用 细胞外基质代谢的调节。肾小球系膜细胞(MC)， 它们通常嵌入在系膜基质区域内， 已被发现对几种肽的生长有反应 因子，包括白细胞介素1(IL-1)、血小板衍生生长 因子(PDFD)和表皮生长因子(EGF)。上一首 研究强调了这些物质对细胞的增殖作用。 各种因素。最近的观察表明，MC分泌 几种可能直接参与细胞周转的蛋白质 肾小球ECM。其中包括一种特定的IV型胶原酶 和一种与组织抑制因子非常相似的蛋白质 金属蛋白酶(TIMP)。在这项提议中，实验是 概述了它将检查潜在的调制效应 四种相关的多肽生长因子(IL-1、PDGF、EGF和 转化生长因子-β)的合成与调控 系膜细胞IV型胶原酶和TIMP蛋白的结合。 这些研究将涉及特定的功能和免疫分析 分泌的蛋白质。此外，生物合成标签和 对细胞内前体的电泳分析将是 已执行。IV型胶原酶与细胞间的相互作用 TIMP的分泌将在几个水平上进行检测，包括 免疫组织化学。这些研究有望扩大我们的 了解系膜细胞的细胞生物学，因为它与 多肽生长因子和细胞外基质代谢因此允许 对肾小球发病机制的进一步认识 受伤。

The glomerular basement membrane and mesangial matrix represent highly specialized forms of extracellular matrix (ECM). Synthesized by the intrinsic glomerular cells, this specialized matrix presumably undergoes normal catabolic turnover. During various pathologic states it is possible that unregulated glomerular ECM catabolism could lead to structural damage to these critical elements. In addition, disorders associated with increased matrix accumulation may be in part due to disturbances of the normal matrix catabolic processes. Evidence obtained from other ECM systems, such as bone, has demonstrated that peptide growth factors play an important role in the cellular regulation of ECM metabolism. Glomerular mesangial cells (MC), which are normally embedded within the mesangial matrix area, have been found to be responsive to several peptide growth factors, including Interleukin-1 (IL-1), platelet-derived growth factor (PDFD), and epidermal growth factor (EGF). Previous studies have emphasized the cellular proliferative effects of these factors. Recent observations have indicated that MC secrete several proteins which may be directly involved in the turnover of the glomerular ECM. These include a specific type IV collagenase and a protein closely resembling the tissue inhibitor of metalloproteinases (TIMP). In this proposal experiments are outlined which will examine the potential modulatory effects of four relevant peptide growth factors, (IL-1, PDGF, EGF and transforming growth factor-beta) on the synthesis and regulation of the mesangial cell type IV collagenase and the TIMP protein. These studies will involve specific functional and immunoassays of secreted proteins. In addition, biosynthetic labelling and electrophoretic analysis of intracellular precursors will be performed. The cellular coordination of type IV collagenase and TIMP secretion will be examined at several levels including immunohistochemistry. These studies will hopefully extend our knowledge of the cell biology of the mesangial cell as it relates to peptide growth factors and ECM metabolism thereby allow for a further understanding of the mechanisms leading to glomerular injury.