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: 10165964
• 负责人: Pui Wen Cheung
• 金额: $ 5.4万
• 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/10165964
• 关键词: AVPR2 gene; Actins; Administrative Supplement; Affect; Biological Assay; Bypass; CRISPR/Cas technology; Cell membrane; Cells; Cirrhosis; Clinic; Communication; Complex; Congestive Heart Failure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dehydration; Disease; Duct (organ) structure; EGF Signaling Pathway; EGF gene; Ensure; Epidermal Growth Factor Receptor; Equilibrium; Funding; Goals; Heart; Homeostasis; In Situ; Inappropriate ADH Syndrome; Interruption; Kidney; Laboratories; Life; Liquid substance; Liver; Liver Cirrhosis; Lung; Maintenance; Maternity leave; Membrane; Mentors; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Parents; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Process; Productivity; Receptor Inhibition; Regulation; Renal function; Research; Research Proposals; Resources; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Symptoms; Time; Tissues; United States National Institutes of Health; Update; Vasopressins; Water; Work; apical membrane; aquaporin-2; career; career development; design; equilibration disorder; experimental study; inhibitor/antagonist; knock-down; knockout animal; novel; preservation; therapy design; trafficking; vasopressin resistant diabetes insipidus

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, and my goal is to deepen our understanding of the crosstalk between VP and EGFR pathways that modulate AQP2, with a long term career goal to characterize the role of this novel signaling pathways in dysregulated water retention observed in patients with SIADH, congestive heart failure and liver cirrhosis, in order to eventually design therapies to alleviate disease symptoms encountered in the clinic. For the last year and a half, I have been making significant progress in dissecting the pertinent pathways between VP and EGFR that regulate water balance. However, as I am focusing on my research career development, life not only brings us surprises, but also concerns about interruption in research progress. Therefore, I am applying for this new NIH-NIDDK Administrative Supplement in order to hire a technician during my maternity leave, expected to span between early to mid-July to early October 2020, in order to preserve or even increase research productivity. The Brown Laboratory, including my mentor Dr. Dennis Brown, my close collaborator Dr. Richard Bouley, and I will maximize the intellectual and technical resources to ensure progress during my leave, and I will remain updated on the progress to resume full productivity upon my return. This research proposal is carved out of Aim 1 of my parent K08, and the proposed experiments are carefully designed and expected to be completed by the end of the supplemental period. Obtaining this supplement funding would provide highly valuable support at this critical time of my research career.

项目概要/摘要 维持水稳态是肾脏的重要功能，对于维持水的平衡至关重要 为了有效地重新吸收水，会释放加压素（VP）以适应陆地生活。 诱导肾脏内水通道蛋白 2 (AQP2) 磷酸化和肌动蛋白细胞骨架重塑 集合管中的主细胞，这增加了 AQP2 顶膜的表达。 AQP2 运输失调导致水平衡紊乱； 膜表达会导致肾性尿崩症 (NDI)，而膜表达的增加会导致肾性尿崩症 (NDI) 质膜 AQP2 与不适当综合征中的液体潴留相关 ADH 分泌（SIADH）、充血性心力衰竭和肝硬化，而 VP/cAMP/PKA 则是。 促进 AQP2 膜运输和水重吸收的主要信号通路 事实上，这个过程要复杂得多，并且可以通过其他信号传导来诱导或抑制 一种这样的“替代”途径涉及表皮生长因子受体。 (EGFR)，其抑制作用可诱导 AQP2 膜积累和磷酸化，类似 到 VP，但绕过 V2R、cAMP 和 PKA，我的目标是加深我们对 VP 和 EGFR 通路之间调节 AQP2 的串扰，长期职业目标是 描述这种新的信号通路在观察到的保水失调中的作用 在患有 SIADH、充血性心力衰竭和肝硬化的患者中，以便最终设计 缓解临床中遇到的疾病症状的疗法。 在过去的一年半里，我在剖析相关问题方面取得了重大进展。 然而，正如我所关注的那样，VP 和 EGFR 之间调节水平衡的途径。 我的科研事业发展、生活给我们带来的不仅是惊喜，还有担忧 因此，我正在申请这个新的 NIH-NIDDK。 行政补充，以便在我的产假期间雇用一名技术人员，预计 跨度为2020年7月上旬至中旬至10月上旬，以保持甚至增加 布朗实验室，包括我的导师丹尼斯·布朗博士，我的密友。 合作者 Richard Bouley 博士和我将最大限度地利用智力和技术资源 确保我休假期间取得进展，我将随时了解全面恢复的进展情况 我回来后的生产力 这个研究计划是根据我父母 K08 的目标 1 制定的， 所提出的实验经过精心设计，预计年底前完成 获得这笔补充资金将提供非常有价值的帮助。 在我研究生涯的关键时刻提供支持。