GENETIC DETERMINANTS IN KIDNEY AND URINARY TRACT DEFECTS

描述（由申请人提供）：对先天性肾脏和泌尿道缺陷发病机制的基本理解对于开发新的诊断和治疗策略至关重要。为了扩展我们在这一领域的研究，我们建议研究胚胎图案缺陷导致四肢和泌尿系统并发异常，这种现象在人类患者中反复观察到。Luxate（Lx）和X连锁多指（Xpl）是两种典型的小鼠突变体，其同时具有肢体缺陷和一系列泌尿系统异常。我们推测，Lx和Xpl突变中断胚胎图案事件与多效性效应，或关键的监管电路共享，泌尿系统的发展和四肢的发展。我们将首先分析Lx和Xpl小鼠，以更好地理解发育过程，当中断时，导致并发缺陷。此外，我们将联合收割机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Xpl突变体中的突变。在我们为Lx和Xpl定义的染色体间隔中，没有已知的涉及先天性肾脏和泌尿道异常的基因仍然是候选基因。因此，突变的鉴定将揭示肾脏发育调控中的新因素。机制研究和突变鉴定工作是相互支持的，旨在说明遗传突变导致先天性肾病的遗传基础和分子机制。公共卫生相关性：泌尿生殖系统缺陷是第二大常见的出生缺陷。先天性肾脏及泌尿道畸形是婴幼儿肾功能衰竭的主要原因。在病因非常不同的患者中，受累肾脏的终末病理变化可能非常相似。治愈的希望在于了解原因和纠正最初的细胞病变。Lx和Xpl突变小鼠同时具有类似于人类“肢端肾综合征”的肢体和肾脏缺陷。在本申请中，我们建议鉴定Lx和Xpl突变体中的基因突变，并揭示这些突变引起并发缺陷的分子机制。从拟议的研究结果将有助于了解遗传因素和泌尿系统和四肢出生缺陷的发病机制。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.