Prune Belly Syndrome: Mechanisms of Filamin A Mutations

李子腹综合症：Filamin A 突变机制

基本信息

批准号：
10468201
负责人：
LINDA A. BAKER
金额：
$ 13.01万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-11-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468201
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&apos 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 Stimulant Stress Stretching 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

项目摘要

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学和分子的知识修剪腹部综合征（PBS）的机制，一种严重的人类多系统先天性泌尿科肌肉和结缔组织缺陷异常。 PBS的Hallmark临床特征包括1）由于腹部骨骼骨骼或不存在的腹部皱纹腹部的三合会。肌肉，2）继发于膀胱平滑肌病理学和3）双侧未固定的睾丸。我们在X链接中发现了三个功能收获的错义突变基因FILAMIN A（FLNA）引起综合征和分离的PBS。 FLNA是丰富的细胞内肌动蛋白 - 跨链接蛋白，充当至关重要的机械传感器，传输力在肌动蛋白和整联蛋白之间进行双向双向，并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，低氧反应，胚胎形态发生和细胞收缩。评估 FLNA突变在小鼠发育和功能方面的作用，我们将研究我们的FLNA收益接触时具有高渗透性PBS表型的功能突变体小鼠妊娠缺氧（AIM 1）。使用最先进的结构和生化技术，我们将表征突变的FLNA蛋白结构以及对结合伴侣的影响（AIM 2）。作为小鼠衍生的FLNA功能获得的膀胱平滑肌细胞具有畸形，功能失调的细胞表型，我们将在细胞下和分子下定义其细胞形式，并且在暴露于环境压力和兴奋剂时的功能（AIM 3）。这个多学科具有独特科学专业知识和高级分子工具集的专家团队将团结起来确定基于FLNA的关键调节机制调节截然肌肉功能和功能障碍导致PBS。这项工作可能填补了我们的重要空白了解FLNA信号传导并产生对逆转录者的更深入的理解肌发生和越来越小的迫切性，整合信号通路，创建动物模型 PBS的大量，并有可能通过指导未来来影响批评者的未来管理理性的治疗设计。