Characterization of Novel Signaling Pathways Involved in Water Balance Disorders

与水平衡紊乱相关的新型信号通路的表征

• 批准号: 10224674
• 负责人: Pui Wen Cheung
• 金额: $ 17.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224674
• 关键词: AVPR2 gene; Actins; Advisory Committees; Affect; Anterior; Arteries; Attenuated; Award; Binding; Biological Assay; Bypass; CRISPR/Cas technology; Cardiac; Cell Culture Techniques; Cell Line; Cell membrane; Cells; Cirrhosis; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Co-Immunoprecipitations; Communication; Communities; Complex; Congestive Heart Failure; Coronary; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Data; Dehydration; Disease; Duct (organ) structure; Epidermal Growth Factor Receptor; Epithelial; Equilibrium; Erlotinib; Female; Forskolin; Functional disorder; Funding; Genes; Goals; Grant; Growth Factor; Guanosine Triphosphate; Heart; Heart failure; Hepatotoxicity; Homeostasis; Hydrolysis; Hyponatremia; Immersion; In Situ; In Vitro; Inappropriate ADH Syndrome; Kidney; Kidney Concentrating Ability; Knockout Mice; Left; Life; Ligation; Liquid substance; Lithium; Liver; Lung; Magnetic Resonance Imaging; Maintenance; Measures; Membrane; Membrane Biology; Mentors; Metabolic; Microscopy; Modeling; Mus; Mutation; Nephrology; Operative Surgical Procedures; Oral; Organ; Osmolalities; Output; Pathology; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Point Mutation; Process; Proteins; Pyrenes; Receptor Inhibition; Receptor Signaling; Regulation; Renal function; Research; Research Training; Rhodamine; Role; Scientist; Secondary to; Serum; Signal Pathway; Signal Transduction; Slice; Small Interfering RNA; Supervision; Symptoms; Techniques; Technology; Testing; Time; Training; Urine; Vasopressins; Ventricular; Water; Western Blotting; Work; apical membrane; aquaporin-2; career development; cell growth regulation; collaborative environment; design; equilibration disorder; heart imaging; immunocytochemistry; in vitro activity; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; member; mutant; novel; polymerization; programs; receptor; rho GTPase-activating protein; role model; targeted treatment; therapy design; tolvaptan; trafficking; vasopressin resistant diabetes insipidus; water channel

PROJECT SUMMARY/ABSTRACT Maintenance of water homeostasis is a vital function of the kidneys and is essential for adaptation to terrestrial life. To reabsorb water effectively, vasopressin (VP) is released to induce aquaporin-2 (AQP2) phosphorylation and actin cytoskeletal remodeling within kidney principal cells in the collecting ducts, which increases apical membrane expression of AQP2. Dysregulation of AQP2 trafficking results in disorders of water balance; decreased AQP2 membrane expression causes nephrogenic diabetes insipidus (NDI), whereas an increase in plasma membrane AQP2 is associated with fluid retention in the syndrome of inappropriate ADH secretion (SIADH), congestive heart failure and cirrhosis. While VP/cAMP/PKA is the major signaling pathway that facilitates AQP2 membrane trafficking and water reabsorption, the process is in fact far more complex, and can be induced or inhibited by other signaling pathways. One such “alternative” pathway involves the epidermal growth factor receptor (EGFR), whose inhibition induces AQP2 membrane accumulation and phosphorylation similar to VP, but bypasses V2R, cAMP and PKA. Therefore, the aims of this grant are to 1) define the mechanism of crosstalk between VP and EGFR signaling pathways that regulate AQP2 trafficking; 2) understand the role of AQP2 phosphorylation on cytoskeletal remodeling, and 3) characterize the roles of novel signaling pathways in dysregulated water retention observed in patients with congestive heart failure, in order to eventually design therapies to alleviate disease symptoms encountered in the clinic. The training plan is progressive and is designed to move the PI Dr. Cheung through an initial stage of completing and expanding her exciting, ongoing work on EGF/VP crosstalk (Aim 1), then moving on to a new aspect of AQP2 cytoskeletal interactions not so far examined in the lab (Aim 2), before finally arriving at Aim 3 on heart/kidney interactions and water balance, which will complete her pathway to independence and be the subject of her first R01 application. Dr. Cheung, supervised by her mentor Dr. Brown, will not only employ existing technologies in the Program in Membrane Biology, but will also acquire important new techniques and research training both from courses listed in her personalized training plan, and from the experts on her advisory committee Drs. Joung (CRISPR/Cas9 gene editing) and Nahrendorf (surgery and mouse imaging for heart failure). For professional career development, in addition to her award-winning mentor Dr. Brown, she has Drs. Sylvie Breton and Jodie Babitt as successful female academic scientist role models. Moreover, the MGH Nephrology Division chief, Dr. Ravi Thadhani will protect her research time from clinical duties, allowing full immersion in her research. Her mentor, members of her scientific advisory committee, her Division chief, the nurturing and collaborative environment in the MGH and Harvard community, will combine with a carefully designed scientific plan to propel her toward her goal of becoming an independent R01 funded academic nephrologist with expertise in inter-organ communications involved in water regulation.

项目总结/文摘