GENETIC DETERMINANTS IN KIDNEY AND URINARY TRACT DEFECTS

描述(由申请人提供)：对先天性肾脏和尿路缺陷的发病机制有一个基本的了解，这对于开发新的诊断和治疗策略至关重要。为了扩大我们在这一领域的研究，我们建议研究胚胎图案缺陷导致肢体和泌尿系统同时异常，这是在人类患者中反复观察到的现象。Luxate(LX)和X连锁多指(Xpl)是两个经典的小鼠突变，同时伴有肢体缺陷和一系列泌尿系统异常。我们假设Lx和Xpl突变中断了胚胎模式事件，对泌尿系统和肢体的发育具有多效性影响，或共享关键调控电路。我们将首先分析Lx和Xpl小鼠，以便更好地了解当中断时导致同时存在缺陷的发育过程。此外，我们将结合成熟的定位克隆方法和最新的基因组分析工具来鉴定Lx和Xp1突变体中的突变。在我们为Lx和Xpl定义的染色体区间中，没有与先天性肾脏和尿路异常有关的已知基因保留下来作为候选基因。因此，对突变的鉴定将揭示肾脏发育调控的新因素。机制研究和突变鉴定工作是相互支持的，旨在阐明基因突变导致先天性肾脏疾病的遗传基础和分子机制这一共同目标。公共卫生相关性：泌尿生殖系统缺陷是第二种最常见的出生缺陷。先天性肾脏和尿路畸形是婴幼儿肾功能衰竭的主要原因。在不同病因的患者中，受影响肾脏的终末病理变化可能非常相似。治愈的希望在于对病因的了解和对最初细胞损害的纠正。Lx和Xpl突变小鼠的四肢和肾脏同时存在缺陷，类似于人类的“Acronenal综合征”。在这一应用中，我们建议鉴定Lx和Xpl突变体中的基因突变，并揭示这些突变导致同时存在缺陷的分子机制。拟议的研究结果将有助于了解泌尿系统和四肢出生缺陷的遗传决定因素和发病机制。这些知识对于开发新的诊断和治疗策略至关重要。

DESCRIPTION (provided by applicant): A fundamental understanding of the pathogenesis of congenital kidney and urinary tract defects is crucial for developing new diagnostic and therapeutic strategies. To extend our research in this area, we propose to study embryonic patterning defects causing concurrent anomalies in the limbs and the urinary system, a phenomenon repeatedly observed in human patients. Luxate (Lx) and X-linked polydactyly (Xpl) are two classical mouse mutants with concurrent limb defects and a range of anomalies in the urinary system. We hypothesize that the Lx and Xpl mutations interrupt embryonic patterning events with pleiotropic effects on, or key regulatory circuits shared by, the development of the urinary system and the development of the limbs. We will first analyze the Lx and Xpl mice for a better understanding of the developmental processes that, when interrupted, cause the concurrent defects. In addition, we will combine the well-established positional cloning methods and the latest genome analysis tools to identify the mutations in the Lx and Xpl mutants. No known genes involved in congenital kidney and urinary tract abnormalities remain as candidates in the chromosomal intervals we have defined for Lx and Xpl. The identification of the mutations will thus reveal novel factors in the regulation of kidney development. The mechanistic studies and the mutation identification efforts are mutually supportive and are aimed at the common goal of illustrating the genetic basis and molecular mechanisms by which genetic mutations cause congenital renal diseases. PUBLIC HEALTH RELEVANCE: Urogenital defects are the second most common birth defects. Congenital kidney and urinary tract malformation is a major cause for renal failure in infants and children. The terminal pathological changes to the affected kidneys can be very similar in patients with very different causes. The hope for cure lies in the understanding of the causes and the correction of the initial cellular lesions. The Lx and Xpl mutant mice have concurrent limb and renal defects that resemble "Acrorenal Syndrome" in humans. In this application, we propose to identify the genetic mutations in the Lx and Xpl mutants and to reveal the molecular mechanisms by which these mutations cause the concurrent defects. Results from the proposed studies will contribute to the understanding of the genetic determinants and pathogenesis of birth defects in both the urinary system and the limbs. Such knowledge is crucial for developing new diagnostic and therapeutic strategies.