Epigenomics in insulin resistance associated overactive bladder

项目摘要/摘要 候选人(Nazema Y.Siddiqui，医学博士，理科硕士)：我的长期目标是改善生活 与膀胱过度活动(OAB)和急迫性尿失禁作斗争的女性 进行创新的转化研究，以改进治疗方案。我的第一步 实现这一目标的重点是患有胰岛素抵抗(IR)的女性，因为这一人群 背负着特别高的OAB患病率。我已经制定了一个培训计划 这是建立在我在泌尿外科方面的临床培训和之前的高级学位 临床研究。K23奖将为我提供必要的指导性实验室 遗传学、表观遗传学方面的培训、保护时间和专门的课程， 生物信息学和分子生物学。环境：我有一支出色的团队 他们将支持我的训练和向独立的过渡。这些人包括Dr。 墨菲，表观基因组学和分子生物学专家；阿蒙森博士， 临床OAB研究；以及卢卡斯博士，他是一位在复杂途径方面具有专长的生物统计学家 分析。我将在杜克大学进行我的培训，这是一个充满活力的学术医学 中心拥有高质量的临床研究基础设施，分子生物学实验室， 和最先进的核心设施，促进翻译研究。研究：我的 提案将检验胰岛素抵抗(IR)通过以下途径促进OAB的假设 参与感觉神经信号传递的尿路上皮基因的DNA甲基化改变。这 假说的基础是：1)膀胱尿路上皮-传入神经信号传递理论 上升到某些类型的OAB；2)数据显示尿路上皮对交通起到“传感器”的作用 膀胱腔和上皮下传入神经纤维之间的物质； 我在OAB-IR患者的无效细胞中的初步数据，在那里我发现改变了 参与信号转导和囊泡转运到细胞的基因甲基化 薄膜。在这项提案中，我将确认差异甲基化在 来自三个特征良好且匹配的女性+/-OAB队列的无效细胞 和/或IR(目标1)。接下来，我将评估与信号有关的基因的差异表达 转导、囊泡运输和感觉神经信号(目标2)。最后，我会 比较我们的部分患者的膀胱粘膜活检组织中的蛋白表达 四个队列(目标3)。有了这些来自这个奖项的数据和技能，我将是独一无二的 适用于将这些机械途径的知识转化为临床 OAB和胰岛素抵抗妇女的新治疗策略的实施。

Project Summary/Abstract Candidate (Nazema Y. Siddiqui, MD, MHSc): My long-term goal is to improve the lives of women struggling with overactive bladder (OAB) and urgency urinary incontinence by conducting innovative translational research to improve therapeutic options. My first step towards that goal focuses on women with insulin resistance (IR) since this population is burdened by an especially high prevalence of OAB. I have developed a training program that builds on my clinical training in urologic conditions and prior advanced degree in clinical research. The K23 Award will provide me with essential mentored laboratory training, protected time, and dedicated coursework in genetics, epigenetics, bioinformatics, and molecular biology. Environment: I have an outstanding team of mentors that will support my training and transition to independence. These include Dr. Murphy, an expert in epigenomics and molecular biology; Dr. Amundsen, an expert in clinical OAB research; and Dr. Lucas, a biostatistician with expertise in complex pathway analyses. I will conduct my training at Duke University, a vibrant academic medical center with high quality clinical research infrastructure, molecular biology laboratories, and state-of-the-art Core Facilities that facilitate translational research. Research: My proposal will test the hypothesis that insulin resistance (IR) contributes to OAB through altered DNA methylation of urothelial genes involved in sensory nerve signaling. This hypothesis is based on: 1) the theory of bladder urothelial-afferent nerve signals giving rise to certain types of OAB; 2) data showing that urothelium acts as a "sensor" to traffic substances between the bladder lumen and suburothelial afferent nerve fibers; and 3) my preliminary data in voided cells of OAB-IR patients, where I discovered altered methylation in genes involved in signal transduction and vesicular trafficking to the cell membrane. In this proposal I will confirm the sites that are differentially methylated in voided cells from three well-characterized and matched cohorts of women +/- OAB and/or IR (Aim 1). Next, I will assess differential expression of genes involved in signal transduction, vesicular trafficking, and sensory nerve signaling (Aim 2). Finally, I will compare protein expression in bladder mucosal biopsies from a subset of patients in our four cohorts (Aim 3). Armed with these data and skills from this award, I will be uniquely suited to translate knowledge of these mechanistic pathways towards clinical implementation of new treatment strategies in women with OAB and insulin resistance.