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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.

项目总结