Prune Belly Syndrome: Mechanisms of Filamin A Mutations

李子腹综合症：Filamin A 突变机制

• 批准号: 10807586
• 负责人: LINDA A. BAKER
• 金额: $ 37.24万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807586
• 关键词: Prune; Belly; Syndrome; Mechanisms; Filamin

Project Summary The overall goal of this project is to expand the knowledge on the genetic basis and molecular mechanisms of Prune Belly Syndrome (PBS), a severe human multi-system congenital urologic anomaly with muscle and connective tissue deficiencies. Hallmark clinical features of PBS include the triad of 1) wrinkled `prune' belly due to hypoplastic or absent abdominal wall skeletal musculature, 2) megacystis secondary to bladder smooth muscle pathology, and 3) bilateral undescended testes. We discovered three gain-of-function missense mutations in the X-linked gene filamin A (FLNA) causing syndromic and isolated PBS. FLNA is an abundant intracellular actin-crosslinking protein that functions as a crucial mechanosensor, transmitting force bidirectionally between actin and integrins as well as binding and regulating other modulatory transmembrane receptors or signaling molecules. FLNA regulates cell shape, adhesion, gene transcription, hypoxic responses, embryonic morphogenesis, and cell contraction. To assess the role of Flna mutations on mouse development and function, we will study our Flna gain-of- function mutant mice that have a highly penetrant PBS-like phenotype when exposed to gestational hypoxia (Aim 1). Using state-of-the-art structural and biochemical techniques, we will characterize mutant FLNA protein structure and the impact on binding partners (Aim 2). As the mouse-derived Flna gain-of-function bladder smooth muscle cells have a dysmorphic, dysfunctional cell phenotype, we will subcellularly and molecularly define their cell form and function when exposed to environmental stress and stimulants (Aim 3). This multidisciplinary expert team with unique scientific expertise and advanced molecular tool sets will unite to identify FLNA-based critical regulatory mechanisms modulating detrusor smooth muscle function and dysfunction leading to PBS. This work may fill an important gap in our understanding of FLNA signaling and yield greater mechanistic understanding of detrusor myogenesis and detrusor underactivity, integrating signaling pathways, creating animal models of PBS, and potentially impacting future management of detrusor underactivity by guiding future rational therapeutic designs.

项目概要 该项目的总体目标是扩展遗传基础和分子生物学知识 梅子腹综合症（PBS）的机制，一种严重的人类多系统先天性泌尿系统疾病 肌肉和结缔组织缺陷的异常。 PBS 的标志性临床特征 包括以下三联征：1）由于腹壁骨骼发育不良或缺失而导致腹部出现皱纹“修剪” 肌肉组织，2) 继发于膀胱平滑肌病理学的巨囊，以及 3) 双侧 睾丸未降。我们在 X 连锁基因中发现了三个功能获得性错义突变 基因细丝蛋白 A (FLNA) 引起综合征并分离 PBS。 FLNA是一种丰富的细胞内 肌动蛋白交联蛋白，充当重要的机械传感器，传递力 肌动蛋白和整合素之间双向，以及结合和调节其他调节 跨膜受体或信号分子。 FLNA 调节细胞形状、粘附、基因 转录、缺氧反应、胚胎形态发生和细胞收缩。评估 Flna 突变对小鼠发育和功能的作用，我们将研究我们的 Flna 增益- 功能突变小鼠在暴露于 妊娠期缺氧（目标 1）。使用最先进的结构和生化技术，我们 将表征突变 FLNA 蛋白结构及其对结合伴侣的影响（目标 2）。作为 小鼠来源的 Flna 功能获得性膀胱平滑肌细胞具有畸形、 功能失调的细胞表型，我们将在亚细胞和分子上定义它们的细胞形式和 当暴露于环境压力和兴奋剂时发挥功能（目标 3）。这个多学科 具有独特科学专业知识和先进分子工具集的专家团队将联合起来 确定基于 FLNA 的调节逼尿肌平滑肌的关键调节机制 导致 PBS 的功能和功能障碍。这项工作可能会填补我们的一个重要空白 了解 FLNA 信号传导并更好地了解逼尿肌的机制 肌生成和逼尿肌活动不足，整合信号通路，创建动物模型 PBS 的研究，并通过指导未来可能影响逼尿肌活动不足的未来管理 合理的治疗设计。