权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The circadian clock protein BMAL and post-translational regulation of ENaC in the kidney

肾脏中生物钟蛋白 BMAL 和 ENaC 的翻译后调节

基本信息

批准号：
10662317
负责人：
Abdel Ayube Alli
金额：
$ 33.55万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662317
关键词：
ARNTL gene Adaptor Signaling Protein Address Aldosterone Antihypertensive Agents Apical Attenuated Binding Biological Assay Biotinylation Blood Pressure Cardiovascular Diseases Caspase Cathepsins B Cause of Death Cell membrane Cells Clock protein Data Distal Duct (organ) structure Ductal Epithelial Cell Electrolytes Equilibrium Essential Hypertension Etiology Excretory function Exhibits Female Fluorescence Resonance Energy Transfer Genes Goals Grant Hour Hypertension In Situ Infusion procedures Investigation Ion Channel Kidney Knockout Mice Knowledge MARCKS gene Mass Spectrum Analysis Measures Mediating Membrane Metabolic Molecular Mus Nephrons Patch-Clamp Techniques Pathogenesis Peptide Hydrolases Phase Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipids Play Post-Translational Protein Processing Post-Translational Regulation Potassium Probability Proteins Proteolysis Proteome Proteomics Regulation Role Sex Differences Sodium Telemetry Testing Therapeutic Time United States Up-Regulation Western Blotting Wild Type Mouse absorption alpha 1-Antitrypsin apical membrane blood pressure control blood pressure reduction blood pressure regulation cardiovascular risk factor circadian circadian pacemaker circadian regulation comparison control density epithelial Na+ channel experimental study male new therapeutic target novel overexpression protein expression renal epithelium salt balance sodium channel proteins transcription factor urinary

项目摘要

ABSTRACT The epithelial sodium channel (ENaC) expressed in the distal tubule and collecting duct is responsible for the final regulation of sodium reabsorption by the kidneys. The myristoylated alanine-rich C kinase substrate (MARCKS) plays an important role as an adaptor protein between the anionic phospholipid PIP2 and ENaC. Both ENaC and MARCKS are positively regulated by the protease cathepsin B. First, our preliminary data demonstrate renal ENaC activity and MARCKS protein expression are positively regulated by the circadian protein BMAL1. Second, our preliminary data show alpha-1 antitrypsin is increased in the BMAL1 knockout mouse kidney compared to the kidney of wild-type mice sacrificed at the same time. Third, our preliminary data show alpha-1 antitrypsin is expressed in the kidney and it strongly inhibits cathepsin B activity and contributes to blood pressure regulation. In this project we will test our hypothesis that the association between renal ENaC and MARCKS, and their function at the apical plasma membrane negatively correlates with alpha-1 antitrypsin expression in a circadian dependent manner. We will perform experiments to investigate proteolysis and apical membrane expression of ENaC and MARCKS, ENaC activity, sodium handling, and blood pressure using male and female BMAL1 knockout mice, alpha-1 antitrypsin knockout mice, alpha-1 antitrypsin overexpressing mice, cathepsin B knockout mice, and wild-type control mice. The successful completion of our proposed studies for this project will reveal new mechanisms underlying the role of BMAL1 in the regulation of renal ENaC and MARCKS and blood pressure control. Our long term goal is to provide a better understanding for the pathogenesis of essential hypertension that can potentially lead to novel drug targets and therapeutics.

摘要

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel.

DOI：
10.3390/biomedicines11020305
发表时间：
2023-01-21
期刊：
Biomedicines
影响因子：
4.7
作者：
通讯作者：

Human Alpha-1 Antitrypsin Attenuates ENaC and MARCKS and Lowers Blood Pressure in Hypertensive Diabetic db/db Mice.

DOI：
10.3390/biom13010066
发表时间：
2022-12-29
期刊：
Biomolecules
影响因子：
5.5
作者：
通讯作者：

Transgenic Mice Overexpressing Human Alpha-1 Antitrypsin Exhibit Low Blood Pressure and Altered Epithelial Transport Mechanisms in the Inactive and Active Cycles.

DOI：
10.3389/fphys.2021.710313
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Liu LP;Gholam MF;Elshikha AS;Kawakibi T;Elmoujahid N;Moussa HH;Song S;Alli AA
通讯作者：
Alli AA

Tempol treatment normalizes membrane expression of epithelial transport proteins in the kidney of salt-loaded hypertensive diabetic db/db mice.

Tempol 治疗可使盐负荷高血压糖尿病 db/db 小鼠肾脏中上皮转运蛋白的膜表达正常化。

DOI：
发表时间：
2023
期刊：
American journal of translational research
影响因子：
2.2
作者：
Dogan,YunusE;Bala,Niharika;Chacko,KevinM;Tuna,KubraM;Alli,AbdelA
通讯作者：
Alli,AbdelA

Dapagliflozin Treatment Augments Bioactive Phosphatidylethanolamine Concentrations in Kidney Cortex Membrane Fractions of Hypertensive Diabetic db/db Mice and Alters the Density of Lipid Rafts in Mouse Proximal Tubule Cells.

DOI：
10.3390/ijms24021408
发表时间：
2023-01-11
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Gholam, Mohammed F.;Liu, Lauren P.;Searcy, Louis A.;Denslow, Nancy D.;Alli, Abdel A.
通讯作者：
Alli, Abdel A.