SPONTANEOUS TUBULOINTERSTITAL NEPHRITIS IN KDKD MICE

已知间质性炎症的严重程度与临床肾脏疾病的严重程度密切相关，但对这些事件涉及的机制知之甚少。 为了获得有关这些途径的信息，该项目将集中在一个自发的，遗传决定的，小鼠间质性肾炎模型。10号染色体上的肾病（kd）基因纯合的小鼠自发地发展成一种间质性肾炎，通常在20周龄左右是致命的。 I类限制性自身免疫反应针对肾小管基底膜抗原。 在本项目中，kd基因将通过定位克隆方法进行研究。 从该基因的克隆和测序中获得的分子信息将用于了解间质性肾炎的诱导机制。 具体的目的是（1）通过遗传重组鉴定kd基因定位在10号染色体上的特定区间，并研究克隆区间中kd的候选基因，（2）检测kd基因与具有C57 BL/6（B6）背景的其他相关基因的相互作用，以及（3）全面表征患病kd/kd小鼠的致肾炎效应T细胞应答。因此，在本项目中，将研究一种独特的自发性、慢性、进行性间质性肾炎动物模型。 该项目的潜在相关性在于，在分子和细胞水平上解释导致肾小管间质损伤的途径，可能导致合理的治疗或预防干预措施的发展。

The severity of interstitial inflammation is known to correlate well with the severity of clinical renal disease, but the mechanisms involved in these events are poorly understood. To gain information about these pathways, this project will focus on a spontaneous, genetically-determined, model of interstitial nephritis in mice. Mice that are homozygous for the kidney disease (kd) gene on chromosome 10 spontaneously develop a form of interstitial nephritis which is usually lethal by about 20 weeks of age. A class I-restricted autoimmune reaction is directed to a tubular basement membrane antigen. In this project, the kd gene will be investigated by means of a positional cloning approach. The molecular information derived from cloning and sequencing this gene will be utilized to understand the mechanisms by which interstitial nephritis is induced. The specific aims are (1) to identify, by genetic recombination, the specific interval on chromosome 10 within which the kd gene maps, and to investigate candidate genes for kd in the cloned interval, (2) to examine the interaction of the kd gene with other relevant genes with the C57BL/6 (B6) background, and (3) to characterize comprehensively the nephritogenic effector T cell response in diseased kd/kd mice. In this project, therefore, a unique animal model of spontaneous, chronic, progressive interstitial nephritis will be studied. The potential relevance of this project is that explication of pathways that lead to tubulointerstitial injury, at the molecular and cellular levels, could lead to the development of rational therapeutic or prophylactic interventions.