PATHOLOGY OF GLOMERULAR MATRIX METABOLISM

进行性肾小球硬化导致终末期肾衰竭是一种 大多数形式的慢性肾小球疾病的统一特征， 大量的文献记载了 在复杂的生物事件中， scoping过程。 该实验室重点研究了 特异性基质金属蛋白酶，即72 kDa明胶酶A（也表示为 基质金属蛋白酶2（MMP-2）在肾小球损伤中的作用。 当正常静止和非增殖时，系膜细胞获得 在炎症状态期间（和培养中）， 这些特征可被定义为“炎性表型”。“这位 这种炎性表型的获得与高表达直接相关。 MMP-2的水平合成。 在最近的研究中， 我们的研究表明，MMP-2直接作用于细胞的合成， 细胞，是至关重要的发展和维护的 炎症表型 因此，我们研究的基本假设是 MMP-2的持续性系膜合成是肾小球硬化的共同特征。 对炎症损伤的反应，这有助于向 scandy州。 考虑到拟议的MMP-2在 发展的系膜炎性表型，更深入的了解 事实上，s调控MMP-2的高水平合成及其机制 由此该酶与肾小球系膜细胞相互作用是必要的。 在这 关于这一点，系膜细胞对MM β-2合成的转录调节是通过细胞外基质介导的。 细胞是独特的，我们已经能够确定一个强大的系膜细胞， 可能决定高水平表达的细胞特异性增强子元件 MMP-2的炎症表型特征。 第二，证据 从这个实验室和其他实验室收集的数据表明， 存在质膜MMP-2结合蛋白，其可能控制细胞的增殖。 酶与周围细胞外基质的相互作用。 这些 这些观察为以下具体目标提供了基础 建议：1.目的：克隆肾小球系膜细胞特异性基质金属蛋白酶-2（MMP-2）， 结合蛋白，其调节酶与 周围细胞外基质;和2. 表征 转录调控机制参与控制高水平的 系膜细胞合成MMP-2代表炎症 表型。 拟议的研究在方法上是互补的， 系膜细胞MMP-2转录调控的问题 在炎性表型的背景下， 这种酶通过特定的膜调节系膜细胞的行为 交互.

Progressive glomerulosclerosis leading to end stage renal failure is a unifying feature of most forms of chronic glomerular disease, and an extensive body of literature has documented the central role of the intrinsic mesangial cell in the complex biologic events which characterize the sclerotic process. This laboratory has focused on the role of a specific matrix metalloproteinase, the 72 kDa gelatinase A (also denoted matrix metalloproteinase 2, MMP-2) ina the evolution of glomerular injury. While normally quiescent and non-proliferative, the mesangial cell acquires during inflammatory states (and in cultaure) a characteristic spectrum of features which may be defined as the "inflammatory phenotype." The acquisition of this inflammatory phenotype is directly coupled with high level synthesis of MMP-2. In recent studies outlined in detail in this proposal, we demonstrated that MMP-2 acts directly upon the synthesizing cells and is critical for the development and maintenance of the inflammatory phenotype. Thus, the fundamental hypothesis of our studies is that persistent mesangial synthesis of MMP-2 is a common feature of the response to inflammatory injury which facilitates the evolution to the sclerotic state. Given the central role proposed for MMP-2 int he development of the mesangial inflammatory phenotype, a deeper understanding of the factos controlling high level MMP-2 synthesis and the mechanisms whereby this enzyme interacts with mesangial cells is warranted. In this regard, the transcriptional regulation of MM{P-2 synthesis by mesangial cells is distinctive and we have been able to identify a strong mesangial cell-specific enhancer element which may dictate the high level expression of MMP-2 characteristic of the inflammatory phenotype. Secondly, evidence gathered from this and other laboratories has indicated that specific plasma membrane MMP-2 binding proteins exist, which may control the interaction of the enzyme with the surrounding extracellular matrix. These observations provide the basis for the following Specific Aims of this proposal: 1. To clone and characterize the specific mesangial cell MMP-2 binding protein which regulates the interaction of the enzyme with the surrounding extracellular matrix; and 2. to characterize the transcriptional regulatory mechanisms involved in the control of high level mesangial cell synthesis of MMP-2 representative of the inflammatory phenotype. The proposed studies are complementary in approach, dealing with the issue of MMP-2 transcriptional regulation by mesangial cells within the context of the inflammatory phenotype and the means by which this enzyme modulates mesangial cellular behavior through specific membrane interactions.