Characterization of Novel Signaling Pathways Involved in Water Balance Disorders

项目摘要/摘要 维持水分平衡是肾脏的一项重要功能，对 适应陆地生活。为了有效地重新吸收水分，血管加压素(VP)被释放到 诱导水通道蛋白-2(AQP2)磷酸化与肾内肌动蛋白细胞骨架重构 集合管中的主细胞，这增加了AQP2的顶膜表达。 AQP2转运失调导致水平衡紊乱；AQP2减少 膜表达导致肾源性尿崩症(NDI)，而膜表达增加 质膜AQP2与不当综合征患者液体滞留的关系 ADH分泌(SIADH)、充血性心力衰竭和肝硬变。而副总裁/阵营/PKA是 促进AQP2膜转运和水分重吸收的主要信号通路， 事实上，过程要复杂得多，并且可以被其他信号诱导或抑制 小路。一种这样的“替代”途径涉及表皮生长因子受体 (EGFR)，其抑制导致AQP2膜积聚和磷酸化类似 到VP，但绕过V2R、CAMP和PKA，我的目标是加深我们对 调节AQP2的VP和EGFR通路之间的串扰，具有长期的职业目标 表征这一新的信号通路在观察到的失调水保持中的作用 在SIADH、充血性心力衰竭和肝硬变患者中，为了最终设计 减轻临床上遇到的疾病症状的疗法。 在过去的一年半里，我在解剖相关的 VP和EGFR之间调节水分平衡的通路。然而，由于我现在关注的是 我的研究生涯发展，生活带给我们的不仅是惊喜，更是牵挂 研究进展的中断。因此，我正在申请这个新的NIH-NIDDK 行政副刊，以便在我的产假期间雇用一名技术员，预计 跨度在2020年7月初至7月中旬至10月初，以保存甚至增加 研究生产力。布朗实验室，包括我的导师丹尼斯·布朗博士，我的近亲 合作者理查德·布利博士和我将最大限度地利用智力和技术资源 确保在休假期间取得进展，我将随时了解进展情况以全面恢复工作 我回来后的工作效率。这项研究提案是根据我父母K08的目标1制定的， 拟议的实验经过精心设计，预计将于年底完成。 补充期的。获得这笔补充资金将提供非常有价值的 在我研究生涯的关键时刻给予支持。

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.