Innovative therapeutic approaches to treat chronic kidney disease

治疗慢性肾脏病的创新治疗方法

• 批准号: 10480353
• 负责人: Andrew S. Terker
• 金额: $ 43.75万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480353
• 关键词: APBA1 gene; Academic Medical Centers; Affect; Animals; Cells; Cellular biology; Chronic Kidney Failure; Dietary Potassium; Disease Progression; Electrophysiology (science); Epithelial Cells; Equilibrium; Funding; Goals; Homeostasis; Injury to Kidney; Kidney; Laboratories; Link; Mediating; Molecular; Muscle; Organ; Pathway interactions; Physiology; Plasma; Potassium; Potassium Channel; Potassium Deficiency; Prevalence; Process; Research; Research Personnel; Role; Signal Transduction; Signaling Molecule; Skeletal Muscle; Therapeutic; Time; cell type; innovation; kidney epithelial cell; kidney metabolism; macrophage; novel; novel strategies; programs; single-cell RNA sequencing

Chronic kidney disease (CKD) has a worldwide prevalence of 10-15% and claims over 130,000 lives annually in the US. Systemic potassium deficiency hastens progression of CKD while higher dietary potassium is protective; however, the mechanistic link between CKD progression and potassium remains entirely unknown. Coordination of total body potassium homeostasis involves both the kidneys and skeletal muscle, with inwardly rectifying potassium (Kir) channels in both organs being critical molecular regulators of this process. I aim to understand how alterations in plasma potassium determine CKD progression. As multiple cell types are involved in the progression of CKD, my focus is on potassium-mediated signaling on proximal tubule epithelial cells and renal macrophages. Using a combination of whole animal kidney physiology, single cell RNA-seq, electrophysiology, and cell biology, I will determine how Kir channels in muscle, proximal tubule cells, and macrophages mediate kidney injury and if these pathways can be targeted as a novel approach to slow CKD progression. I propose to (1) determine how the basolateral potassium channel, Kir4.2, in the proximal tubule mediates kidney injury and metabolism, (2) determine how Kir2.2 in macrophages affect kidney injury, and (3) determine how Kir2.1 and Kir2.2 in skeletal muscle affect systemic potassium balance and in turn, kidney injury. Successful completion of this proposal will change our fundamental understanding of Kir channels as regulators of potassium signaling and identify Kir4.2, Kir2.1, Kir 2.2, and their related pathways as targets for CKD treatment. Further, it will define a muscle-kidney axis linked by plasma potassium as the signaling molecule. This project is my first as an independent investigator and will be supported by significant institutional support from Vanderbilt University Medical Center. This includes funding, laboratory space, and protected research time to establish my research program focused on potassium signaling via Kir channels and CKD.

慢性肾脏疾病（CKD）在全球范围内的患病率为10-15%，每年夺去超过130，000人的生命， 美方系统性缺钾可加速慢性肾脏病的进展，而高钾饮食则具有保护作用; 然而，CKD进展和钾之间的机制联系仍然完全未知。协调 全身钾稳态的影响包括肾脏和骨骼肌， 钾（Kir）通道是这一过程的关键分子调节剂。我的目标是了解 血浆钾的变化如何决定CKD的进展。由于多种细胞类型参与了 CKD的进展，我的重点是钾介导的信号对近端小管上皮细胞和肾脏 巨噬细胞使用整个动物肾脏生理学、单细胞RNA-seq、电生理学的组合， 和细胞生物学，我将确定肌肉，近端小管细胞和巨噬细胞中的Kir通道如何介导 肾损伤以及这些途径是否可以作为减缓慢性肾病进展的新方法。我建议 (1)确定近端小管中的基底外侧钾通道Kir4.2如何介导肾损伤， 代谢，（2）确定巨噬细胞中Kir2.2如何影响肾损伤，以及（3）确定Kir2.1和 骨骼肌中的Kir2.2影响全身钾平衡，进而影响肾损伤。成功完成 这一提议将改变我们对Kir通道作为钾信号调节器的基本认识 并鉴定Kir4.2、Kir2.1、Kir 2.2及其相关通路作为CKD治疗的靶点。此外，它将定义 肌肉-肾轴通过作为信号分子的血浆钾连接。这个项目是我作为一个 独立调查员，并将得到范德比尔特大学的重要机构支持 医学中心这包括资金、实验室空间和受保护的研究时间来建立我的研究 该项目专注于通过Kir通道和CKD的钾信号传导。