A Genetic Model of Urogenital Development & Obstruction

泌尿生殖发育的遗传模型

• 批准号: 7239635
• 负责人: KIRK M. MCHUGH
• 金额: $ 29.62万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239635
• 关键词: Affect; Animals; Bladder; Bladder Diseases; Bladder Dysfunction; Candidate Disease Gene; Chemistry; Child; Chronic Kidney Failure; Clinical; Complex; Cytogenetics; Defect; Development; Disease; Drug Formulations; Embryo; End stage renal failure; Evaluation; Future; Gender; Gene Transfer Techniques; Genes; Genetic; Genetic Models; Genitourinary system; Genomics; Goals; In Vitro; Molecular; Morbidity - disease rate; Mus; Muscle Development; Obstruction; Output; Pathogenesis; Pathway interactions; Phenotype; Prevalence; Process; Quality of life; Secondary to; Serum; Site; Smooth Muscle; Study models; Techniques; Therapeutic; Transgenes; Ultrasonography; United States; Urine; base; cost; day; functional outcomes; in utero; male; mutant mouse model; postnatal; urinary tract obstruction

DESCRIPTION (provided by applicant): Diseases of the urinary bladder affect an estimated 35 million people in the United States, with end-stage renal failure in children alone estimated to cost over $15 billion dollars annually. Despite the prevalence of bladder disease, little is currently known regarding the mechanisms controlling these processes. We have identified a unique insertional mutant mouse model that develops in utero megabladder resulting in variable hydroureteronephrosis and chronic renal failure secondary to obstructive uropathy. These animals, designated mgb for megabladder, possess a primary defect in bladder smooth muscle development that is apparent by embryonic day 15, and whose functional outcome appears gender-influenced. Clarifying the precise developmental and functional defects found in mgb mice and determining the genetic locus responsible for these abnormalities will provide valuable information regarding the molecular mechanisms controlling urogenital development and disease. The long-term objectives of this project are to gain a better understanding of the complex molecular pathways that control normal bladder development and pathogenesis, In Specific Aim 1 we propose to complete the characterization of the mgb phenotype using both histological and immunohistochemical techniques. In Specific Aim 2, we intend to identify the genetic locus responsible for the mgb phenotype using an overlapping, multifaceted approach that includes cytogenetic characterization of the transgene insertion site, identification of genomic break points, expression analysis of candidate genes, and phenotype rescue by reverse transgenesis. Finally, in Specific Aim 3, we will perform morphometric analysis, in vitro cystometry and ultrasound to characterize the functional state of mgb mice, and correlate this to the clinical state of the animals using urine output and serum chemistry. Completion of these studies will significantly enhance our understanding of normal bladder development and pathogenesis, and permit the formulation and evaluation of therapeutic strategies in the future.

描述（由申请人提供）：在美国，膀胱疾病影响着大约 3500 万人，仅儿童的终末期肾衰竭每年就造成超过 150 亿美元的损失。尽管膀胱疾病很普遍，但目前对控制这些过程的机制知之甚少。我们已经确定了一种独特的插入突变小鼠模型，该模型在子宫巨膀胱中发育，导致可变的输尿管肾积水和继发于梗阻性尿路病的慢性肾功能衰竭。这些动物被命名为“mgb”，意思是“巨膀胱”，它们在膀胱平滑肌发育方面存在主要缺陷，这种缺陷在胚胎第 15 天时就很明显，而且其功能结果似乎受到性别的影响。澄清 mgb 小鼠中发现的精确发育和功能缺陷并确定导致这些异常的遗传位点将为控制泌尿生殖发育和疾病的分子机制提供有价值的信息。该项目的长期目标是更好地了解控制正常膀胱发育和发病机制的复杂分子途径，在具体目标 1 中，我们建议使用组织学和免疫组织化学技术完成 mgb 表型的表征。在具体目标 2 中，我们打算使用重叠、多方面的方法来识别负责 mgb 表型的遗传位点，包括转基因插入位点的细胞遗传学特征、基因组断裂点的识别、候选基因的表达分析以及通过反向逆向拯救表型转基因。最后，在具体目标 3 中，我们将进行形态测量分析、体外膀胱测压和超声来表征 mgb 小鼠的功能状态，并使用尿量和血清化学将其与动物的临床状态相关联。这些研究的完成将显着增强我们对正常膀胱发育和发病机制的理解，并允许未来治疗策略的制定和评估。