SPONTANEOUS TUBULOINTERSTITAL NEPHRITIS IN KDKD MICE

已知间质炎症的严重程度与临床肾脏疾病的严重程度有很好的相关性，但这些事件涉及的机制尚不清楚。为了获得有关这些途径的信息，该项目将专注于一种自发的、由基因决定的小鼠间质性肾炎模型。10号染色体上肾脏疾病(Kd)基因纯合的小鼠会自发地发展成一种间质性肾炎，这种肾炎通常在20周大的时候是致命的。针对管状基底膜抗原的I类限制性自身免疫反应。在这个项目中，将通过定位克隆的方法来研究kd基因。克隆和测序该基因所获得的分子信息将被用来理解间质性肾炎的诱发机制。其具体目的是(1)通过基因重组确定kd基因在10号染色体上定位的特定区间，并在克隆区间内研究kd候选基因；(2)检测kd基因与其他具有C57BL/6(B6)背景的相关基因的相互作用；(3)全面表征疾病kd/kd小鼠的肾性效应T细胞反应。因此，在本项目中，将研究一种独特的自发性、慢性、进行性间质性肾炎的动物模型。这个项目的潜在相关性是，在分子和细胞水平上解释导致肾小管间质损伤的途径，可以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.