RENAL FIBROSIS

肾脏纤维化是一种活跃的过程，由多种形式的 肾脏损伤，它与肾脏组织的永久性丢失有关， 因此结果很差。我们假设，预防 疤痕可以使正常的肾组织在大多数形式的 肾损伤。因此，我们需要了解胶原蛋白的代谢。 正常和不正常的肾脏，因此可以开发出 抑制或延缓疤痕形成过程。为了解决这个问题，我们有 兔抗肾小球基底膜模型胶原代谢的详细分析 可复制的疾病在间质和间质中都会发展为纤维化 肾小球室。兔的原位杂交分析 α2(I)前胶原mRNA表明以前未被识别的细胞， 血管外膜细胞(VAC)是一种主要的细胞，负责 模型中的疤痕形成过程。以证实这一假设，并提出 在本应用程序中，我们将确定其他胶原mRNA是否 在疤痕形成过程的进化过程中以类似的方式分布 在模型中。我们将鉴定和鉴定趋化因子 负责从血管周围外膜吸引VAC 小室进入间质，然后到达肾小球周围 从那里可以进入鲍曼的空间。我们会 从正常和疤痕形成的肾脏中鉴定VAC，这样我们就可以 了解哪些因素调节其胶原合成、趋化性和 细胞分裂。我们将在体内确定转化生长因子-β是否耗尽， 我们之前已经证明它是驱动胶原蛋白的主要因素 在模型中合成，防止疤痕和保护肾功能。 最后，我们将测试我们可以预测哪些人将 早期通过检测胶原蛋白的mRNA水平而形成严重的瘢痕 疤痕形成之前发生的一系列事件。如果我们可以 预测谁会留下疤痕，并制定预防策略 疤痕，我们将开始开发一种抗疤痕的基础 可应用于严重形式的炎症性疾病的策略 在男性中，包括严重的肾小球肾炎、间质性肾炎和 移植排斥反应，通常会导致永久性肾功能丧失 结构和功能。

Fibrosis in the kidney is an active process triggered by many forms of renal injury and it is associated with permanent loss of renal tissue, and therefore with poor outcome. We hypothesize that prevention of scarring would allow normal renal tissue to recover in most forms of renal injury. We therefore need to understand collagen metabolism in the normal and abnormal kidney so that strategies can be developed that would inhibit or retard the scarring process. To address this question we have analyzed in detail collagen metabolism in a rabbit model of anti-GBM disease that reproducibly goes on to fibrosis both in interstitial and glomerular compartments. Analysis using in situ hybridization for rabbit alpha2(I) procollagen mRNA indicates that a previously unrecognized cell, the vascular adventitial cell (VAC), is a major cell responsible for the scarring process in the model. To confirm this hypothesis and proposed in this application we will determine whether other collagen mRNAs are distributed in a similar manner during evolution of the scarring process in the model. We will characterize and identify the chemotactic factors responsible for attracting the VAC from the perivascular adventitial compartment out into the interstitium and thence to the periglomerular region from where it gains access to Bowman's space. We will characterize the VAC from normal and scarring kidney so that we can understand what factors regulate its' collagen synthesis, chemotaxis and cell division. We will determine in vivo whether depletion of TGF-beta, which we have previously shown to be the major factor driving collagen synthesis in the model, prevents scarring and preserves renal function. Finally we will test the idea that we can predict which individuals will develop severe scarring by measuring mRNA levels for collagens early in the sequence of events before scar formation has occurred. If we can predict who will go on to scar, and develop strategies that prevent scarring, we will have begun to develop the basis for an anti-scarring strategy that could be applied to severe forms of inflammatory diseases in man, including severe glomerulonephritis, interstitial nephritis and transplant rejection, that commonly result in permanent loss of renal structure and function.