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发病机制的基本了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，我们建议研究导致四肢和泌尿系统同时异常的胚胎模式缺陷，这一现象在人类患者中反复观察到。Luxate （Lx）和X-linked polydactyly （Xpl）是两种典型的小鼠突变体，并发肢体缺陷和泌尿系统的一系列异常。我们假设Lx和Xpl突变中断了胚胎模式事件，这些事件对泌尿系统的发育和四肢的发育具有多向性影响或共享的关键调节回路。我们将首先分析Lx和Xpl小鼠，以便更好地理解当中断时导致并发缺陷的发育过程。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Xpl突变体的突变。在我们为Lx和Xpl定义的染色体间隔中，没有已知的与先天性肾脏和尿路异常有关的基因作为候选基因。这些突变的鉴定将揭示调控肾脏发育的新因素。机制研究和突变鉴定工作是相互支持的，其共同目标是阐明遗传突变导致先天性肾脏疾病的遗传基础和分子机制。公共卫生相关性：泌尿生殖缺陷是第二常见的出生缺陷。先天性肾和尿路畸形是婴儿和儿童肾功能衰竭的主要原因。在病因不同的患者中，受影响肾脏的终末病理变化可能非常相似。治愈的希望在于了解病因和纠正最初的细胞病变。Lx和Xpl突变小鼠同时存在肢体和肾脏缺陷，类似于人类的“肢端肾综合征”。在这个应用中，我们建议鉴定Lx和Xpl突变体的基因突变，并揭示这些突变导致并发缺陷的分子机制。所提出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.