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ENaC regulation and its role in blood pressure homeostasis

ENaC 调节及其在血压稳态中的作用

基本信息

批准号：
10338091
负责人：
Annet Kirabo
金额：
$ 75.35万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338091
关键词：
Abbreviations Address Affect Aldosterone Alleles Amiloride Angiotensin II Animal Model Antigens Argipressin Binding Blood Pressure Bone Marrow Bone Marrow Transplantation Cells Clinical Databases Dendritic Cell Pathway Dendritic Cells Diet Disease Distal Electrolytes Essential Hypertension Excretory function Extracellular Domain Extracellular Fluid Family Genes Genetic Genetically Engineered Mouse Health Homeostasis Hormones Human Hypertension Hypotension Individual Inflammation Inflammatory Intake Ion Channel Kidney Knock-in Mouse Link Liquid substance Mendelian disorder Modification Mouse Strains Mus Myeloid Cells NADPH Oxidase Nephrons Palmitates Peptide Hydrolases Post-Translational Protein Processing Probability Process Production Proteolysis Regulation Risk Role Signal Pathway Single Nucleotide Polymorphism Site Sodium Superoxides System T cell differentiation Trans-Omics for Precision Medicine Variant blood pressure control blood pressure elevation blood pressure regulation cell type cytokine dbSNP dietary dietary salt epithelial Na+ channel experimental study extracellular gain of function high salt diet in vivo insight loss of function loss of function mutation member mutant novel palmitoylation response salt sensitive hypertension targeted treatment urinary

项目摘要

Epithelial Na+ channels (ENaCs) are one of several key Na+ transporters in the aldosterone-sensitive distal nephron (ASDN) that participate in the reabsorption of filtered Na+ in a highly regulated manner. These Na+ transporters have important roles in the regulation of extracellular fluid volume and blood pressure. In addition to the ASDN, ENaCs are expressed at other sites that influence blood pressure. For example, ENaCs are expressed in antigen presenting dendritic cells where they appear to have a role in linking a high salt diet, inflammation and blood pressure. Proposed studies in Aim 1 will use a novel mouse ENaC gamma subunit hypomorph to elucidate the roles of ENaC in myeloid cells (dendritic cells) and non-myeloid cells (e.g., principal cells of the ASDN) in the blood pressure response to a high salt diet. Rare gain- or loss-of-function mutations within ENaC subunits have been described in Mendelian disorders characterized by hypertension or hypotension, respectively. Gene sequencing efforts have revealed hundreds of non-synonymous single nucleotide variants (nsNSVs) in human genes the encoding alpha, beta and gamma subunits. An increasing number of functional nsNSVs have been identified, although the potential contributions of the vast majority of these variants to human health and disease states are unknown. We have identified specific nsSNVs in the large extracellular regions of ENaC subunits that either enhance or inhibit channel activity by altering a regulatory response to extracellular Na+, referred to as Na+ self-inhibition. We have introduced specific gain- or loss-of-function variants into mice, corresponding to known functional human ENaC nsSNVs. Studies in Aim 2 will determine whether a gain-of-function variant predisposes mice to salt-sensitive hypertension, and whether a loss-of-function variant protects against salt-sensitive hypertension. Cleavage of ENaC subunits by specific proteases, and modification of ENaC subunits by the addition of palmitate, activate the channel. We have created novel mouse strains expressing ENaC subunits that lack key sites for protease cleavage or palmitoylation. Proposed studies in Aim 3 will define the roles of these regulatory processes in the adaptation to a low or high salt diet. The results from these studies will provide important insights regarding the role of dendritic cell ENaC in the blood pressure response to dietary salt in mice, demonstrate that ENaC variants that affect channel function by altering Na+ self-inhibition affect blood pressure in mice, and demonstrate the functional roles of ENaC subunit proteolysis and palmitoylation in mice.

上皮Na+通道（Epithelial Na + channels，ENaCs）是醛固酮敏感性远端内皮细胞的重要Na+转运体之一。肾单位（ASDN）以高度调节的方式参与过滤的Na+的重吸收。这些Na+ 转运蛋白在调节细胞外液体积和血压中具有重要作用。此外对于ASDN，ENaC在影响血压的其他部位表达。例如，ENaC是在抗原呈递树突细胞中表达，它们似乎在连接高盐饮食，炎症和血压。目标1中的拟议研究将使用一种新的小鼠ENaC γ亚基亚型以阐明ENaC在骨髓细胞（树突细胞）和非骨髓细胞（例如， ASDN的主要细胞）在血压对高盐饮食的反应中。罕见功能获得或丧失 ENaC亚基内的突变已经在以高血压或高血压为特征的孟德尔疾病中描述，低血压，分别。基因测序工作已经揭示了数百个非同义的单在人类基因中的核苷酸变体（nsNSV）编码α、β和γ亚基。越来越已经确定了许多功能性nsNSV，尽管绝大多数nsNSV的潜在贡献这些变异对人类健康和疾病状态的影响是未知的。我们已经确定了特定的nsSNV在 ENaC亚单位的大的胞外区域，通过改变通道的分子结构来增强或抑制通道活性。对细胞外Na+的调节反应，称为Na+自抑制。我们引入了特定增益- 或功能丧失变体植入小鼠，对应于已知的功能性人ENaC nsSNV。研究目的 2将确定功能获得性变体是否使小鼠易患盐敏感性高血压，功能丧失型变异体是否能预防盐敏感性高血压。ENaC亚基的切割特定的蛋白酶和通过添加棕榈酸酯修饰ENaC亚基激活通道。我们已经创造了表达ENaC亚基的新型小鼠品系，这些亚基缺乏蛋白酶切割的关键位点，棕榈酰化目标3中拟议的研究将确定这些调节过程在适应中的作用低盐或高盐饮食。这些研究的结果将提供有关药物作用的重要见解树突状细胞ENaC在小鼠对饮食盐的血压反应中，证明ENaC变体，通过改变Na+自我抑制影响通道功能，影响小鼠血压，并证明 ENaC亚基蛋白水解和棕榈酰化在小鼠中的功能作用。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hypertensive heart disease: risk factors, complications and mechanisms.

DOI：
10.3389/fcvm.2023.1205475
发表时间：
2023
期刊：
FRONTIERS IN CARDIOVASCULAR MEDICINE
影响因子：
3.6
作者：
Masenga, Sepiso K.;Kirabo, Annet
通讯作者：
Kirabo, Annet

Meet the Novel Players in Hypertensive Kidney Disease: Septin4 and SIRT2.

DOI：
10.1161/circresaha.123.322552
发表时间：
2023-03
期刊：
Circulation research
影响因子：
20.1
作者：
S. Dikalov;Annet Kirabo
通讯作者：
S. Dikalov;Annet Kirabo

In Memoriam: Fernando Elijovich.

悼念：费尔南多·埃利乔维奇。

DOI：
10.1161/hypertensionaha.122.20541
发表时间：
2023
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
0
作者：
Ertuglu,LaleA;Laffer,CherylL;Kirabo,Annet
通讯作者：
Kirabo,Annet

HIV-Host Cell Interactions.

HIV - 宿主细胞相互作用。

DOI：
10.3390/cells12101351
发表时间：
2023-05-09
期刊：
CELLS
影响因子：
6
作者：
Masenga, Sepiso K.;Mweene, Bislom C.;Luwaya, Emmanuel;Muchaili, Lweendo;Chona, Makondo;Kirabo, Annet
通讯作者：
Kirabo, Annet