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Cell Biology of Vasopressin-induced Water Channels-Research Supplement

加压素诱导的水通道的细胞生物学-研究补充

基本信息

批准号：
10835229
负责人：
Dennis Brown
金额：
$ 7.78万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10835229
关键词：
Actin-Binding Protein Actins Address Affect Animals Biological Assay Cell membrane Cells Cellular biology Clinical Complex Congestive Heart Failure Data Dehydration Development Disease EGF gene EGFR inhibition Electrolytes Endocytosis Epidermal Growth Factor Receptor Epithelial Cells Equilibrium Exocytosis Goals Homeostasis Hypertension Kidney Kidney Diseases Ligands Liquid substance Membrane Molecular Participant Pathway interactions Pharmaceutical Preparations Phosphorylation Physiology Process Production Proteins Public Health RPS6KA gene Receptor Activation Regulation Regulatory Pathway Research Ribosomal Protein S6 Kinase Signal Pathway Signal Transduction Techniques Translating Urine Vasopressin Receptor Vasopressins War Water Work antidiuretic aquaporin-2 cohort enzyme activity equilibration disorder ezrin genetic regulatory protein kidney cell live cell imaging novel novel therapeutics pharmacologic superresolution microscopy trafficking vasopressin resistant diabetes insipidus water channel

项目摘要

Because of a lack of safe, effective and specific treatments for disorders of water balance, the ultimate goal of our work is to identify novel intracellular pathways by which plasma membrane accumulation of the aquaporin 2 water channel (AQP2) in kidney principal cells can be normalized in the absence of a properly functioning vasopressin receptor (V2R) signaling pathway. The overall objective of this proposal is to dissect newly- identified aquaporin 2 (AQP2) trafficking and regulatory pathways in order to provide actionable, basic information that can be translated into cell-specific clinical advances for the treatment of these conditions. Nephrogenic diabetes insipidus (NDI) is caused by renal insensitivity to VP, and results in excessive urine production, whereas water retention, often a result of inappropriate VP secretion, occurs in conditions such as congestive heart failure. Aim 1 addresses the hypothesis that AQP2 itself directs its intracellular trafficking itinerary as an “active” cargo protein rather than a passive bystander. We propose that AQP2 “catalyzes” compartment-specific actin remodeling via direct and indirect interactions with different cohorts of actin- regulatory proteins. These include actin itself, the Arp2/3 actin remodeling complex during exocytosis, and the actin binding protein ezrin during endocytosis. Aim 2 will identify the cellular crosstalk mechanism(s) by which a tug-of-war between the vasopressin receptor (VP/V2R - positive action) and epidermal growth factor receptor (EGF/EGFR - negative effect) regulate AQP2 trafficking and water balance. We will first explore how EGF and other EGFR ligands inhibit the antidiuretic effect of VP by receptor activation and downstream signaling. Then we will ask how inhibition of the EGFR pathway results in VP-independent AQP2 phosphorylation and membrane accumulation by activating a non-canonical kinase, P90 ribosomal S6 kinase (RSK). Techniques central to the proposed work include the molecular characterization of protein interactions, advanced super resolution microscopy and live cell imaging, enzyme activity assays, expression of modified proteins in cultured epithelial cells, and whole animal physiology. Understanding novel cellular mechanisms of AQP2 regulation and defining more specific participants in intracellular signaling will open unexplored avenues of research into the regulation of fluid and electrolyte homeostasis. We expect that our data will allow the development of more selective and cell specific pharmacological strategies to regulate AQP2 trafficking in water balance disorders.

由于缺乏安全、有效和专门的治疗水平衡失调的方法，最终的目标是

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ILK and cytoskeletal architecture: an important determinant of AQP2 recycling and subsequent entry into the exocytotic pathway.

DOI：
10.1152/ajprenal.00336.2016
发表时间：
2016-10
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
Fahmy A. Mamuya;José Luis Cano-Peñalver;Wei Li;D. Rodríguez Puyol;M. Rodriguez Puyol;Dennis Brown;S. de Frutos;H. Lu
通讯作者：
Fahmy A. Mamuya;José Luis Cano-Peñalver;Wei Li;D. Rodríguez Puyol;M. Rodriguez Puyol;Dennis Brown;S. de Frutos;H. Lu

Sex-dependent differences in water homeostasis in wild-type and V-ATPase B1-subunit deficient mice.

野生型和 V-ATPase B1 亚基缺陷小鼠水稳态的性别依赖性差异。