Prune Belly Syndrome: Mechanisms of Filamin A Mutations

李子腹综合症：Filamin A 突变机制

• 批准号: 10264077
• 负责人: LINDA A. BAKER
• 金额: $ 55.61万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264077
• 关键词: 2 year old; Actins; Adhesions; Affect; Age; Amniotic Fluid; Animal Model; Bilateral; Binding; Binding Sites; Biochemical; Bladder; Bladder Control; Bladder Dysfunction; C-terminal; Calpain; Catheterization; Cell Shape; Cell physiology; Cells; Cessation of life; Clinical; Complex; Connective Tissue; Cryptorchidism; DNA Sequence Alteration; Deposition; Development; Dialysis procedure; Dimerization; Dysplasia; Embryo; Exposure to; Extracellular Matrix; F-Actin; FLNA gene; Fetal Lung; Focal Adhesions; Froehlich' s Syndrome; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Histologic; Human; Human Genetics; Hydronephrosis; Hypoxia; Immunoglobulins; Integrin Binding; Integrin beta Chains; Integrins; Kidney; Kidney Transplantation; Knowledge; Lead; Life; Ligand Binding; Link; Masks; Mediating; Medical Care Costs; Microscopy; Missense Mutation; Molecular; Molecular Conformation; Morbidity - disease rate; Morphogenesis; Mus; Muscle; Muscle Contraction; Muscle Development; Muscle function; Mutant Strains Mice; Mutation; N-terminal; Operative Surgical Procedures; Organ; Pathology; Patients; Pharmacotherapy; Phenotype; Principal Investigator; Prognosis; Proteins; Publications; Quality of life; Regulation; Respiratory System; Rod; Role; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Source; Stress; Stretching; Structure; Survivors; Syndrome; Tail; Techniques; Testing; Therapeutic; Thick; Triad Acrylic Resin; Ureter; Urethra; Urinary tract; Urine; Urologic Diseases; Work; abdominal wall; base; bladder surgery; congenital anomaly; design; detrusor underactivity; developmental genetics; disability; experience; fetal; filamin; gain of function; genetic variant; gestational hypoxia; ineffective therapies; loss of function; lung development; male; mechanotransduction; monomer; mouse development; multidisciplinary; mutant; myogenesis; postnatal; pressure; programs; protein crosslink; protein function; protein structure; receptor; renal damage; response; skeletal; stillbirth; structural biology; tool; treatment strategy; urologic

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.

项目摘要 该项目的总体目标是扩大遗传基础和分子生物学方面的知识， 李腹综合征（PBS），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）由于发育不全或腹壁骨骼缺失而导致的皱皱的“修剪”腹部 肌肉组织，2）继发于膀胱平滑肌病理学的巨大膀胱，和3）双侧 隐睾我们在X染色体连锁突变中发现了三个功能获得性错义突变。 基因细丝蛋白A（FLNA）引起综合征和分离的PBS。FLNA是一种丰富的细胞内 肌动蛋白交联蛋白，作为一个重要的机械传感器， 肌动蛋白和整合素之间的双向调节，以及结合和调节其他调节因子， 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获得- 功能突变小鼠，当暴露于 妊娠缺氧（目的1）。利用最先进的结构和生化技术，我们 将表征突变FLNA蛋白结构和对结合伴侣的影响（目的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，我们将亚细胞和分子定义他们的细胞形式， 当暴露于环境压力和刺激物时（目标3）。这种多学科 拥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， 鉴定基于FLNA调节逼尿肌平滑肌的关键调节机制 功能和功能障碍导致PBS。这项工作可能填补了我们的一个重要空白。 了解FLNA信号传导，并对逼尿肌的机制有更深入的了解 肌生成和逼尿肌活动不足，整合信号通路，创建动物模型 PBS，并通过指导未来的逼尿肌活动不足， 合理的治疗设计