PATHOLOGY OF GLOMERULAR MATRIX METABOLISM

进行性肾小球硬化导致终末期肾功能衰竭 大多数形式的慢性肾小球疾病的统一特征，以及 大量的文献记载了 固有系膜细胞在复杂的生物事件中的特征 硬化过程。本实验室的重点是 特异性基质金属蛋白酶，72 kDa明胶酶A(又称 基质金属蛋白酶-2在肾小球损伤演变中的作用 当通常处于静止和非增殖状态时，系膜细胞获得 在炎症状态(和培养中)，一种特征光谱 可定义为“炎症性表型”的特征。这个 这种炎症性表型的获得直接伴随着高 水平合成基质金属蛋白酶-2。在最近的研究中详细介绍了这一点 建议，我们证明了基质金属蛋白酶-2直接作用于合成 细胞，并且对于开发和维护 炎症表型。因此，我们研究的基本假设是 肾小球系膜上持续合成基质金属蛋白酶-2是 对炎性损伤的反应，促进向 硬化状态。鉴于所提议的基质金属蛋白酶-2的核心作用 对系膜炎症表型的发展有了更深的认识 基质金属蛋白酶-2高水平合成的调控因素及机制研究进展 因此，这种酶与系膜细胞相互作用是必要的。在这 关于系膜蛋白对MM{P-2合成的转录调控 细胞是独特的，我们已经能够识别出一个强大的系膜 可能决定高水平表达的细胞特异性增强子元件 炎性表型特有的基质金属蛋白酶-2的表达。第二，证据 从这个实验室和其他实验室收集的数据表明，具体的 质膜基质金属蛋白酶-2结合蛋白的存在，可能控制 酶与周围细胞外基质的相互作用。这些 观察结果为以下具体目标提供了基础 建议：1.克隆并鉴定特异性系膜细胞基质金属蛋白酶-2 一种结合蛋白，它调节酶与细胞之间的相互作用 围绕细胞外基质；以及2.表征细胞外基质 参与高水平调控的转录调控机制 以系膜细胞合成的基质金属蛋白酶-2为代表的炎性细胞 表型。拟议的研究在方法、处理方式上是互补的 肾小球系膜细胞对基质金属蛋白酶-2的转录调控 在炎症表型和手段的背景下 这种酶通过特定的膜调节系膜细胞的行为。 互动。

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.