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Adrenal cell ATP1A1 mutations and mechanisms of aldosterone biosynthesis

肾上腺细胞ATP1A1突变与醛固酮生物合成机制

基本信息

批准号：
9813129
负责人：
Celso Enrique Gomez-Sanchez
金额：
$ 31.88万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813129
关键词：
ATP phosphohydrolase ATP1A1 gene Acute Address Adrenal Gland Diseases Adrenal Glands Adult Affect Age Aging Aldosterone Anabolism Angiotensin II Bilateral Ca(2+)-Transporting ATPase Calcium Calcium Channel Cardiovascular Diseases Cardiovascular system Cell Proliferation Cell membrane Cells Cessation of life Chloride Channels Chronic Clinic Complex Corticotropin Coupled Defect Development Enzymes Essential Hypertension Functional disorder Gene Mutation Genes Growth Human Hyperaldosteronism Hyperplasia Hypertension Hypertrophy Incidence Individual Inflammation Kidney Lead MAP Kinase Gene Membrane Mineralocorticoid Receptor Monoclonal Antibodies Morbidity - disease rate Mutation Na(+)-K(+)-Exchanging ATPase Oral Ouabain Pathway interactions Patients Pattern Peptides Plasma Play Potassium Potassium Channel Production Pump Regulation Reporting Role SRC gene Secondary Hypertension Severities Signal Pathway Signal Transduction Signal Transduction Alteration Sodium Chloride Sodium-Calcium Exchanger Somatic Mutation Steroid biosynthesis Testing Zona Glomerulosa adenoma beta catenin cardiovascular risk factor cellular transduction gain of function high risk inward rectifier potassium channel loss of function loss of function mutation low renin hypertension men mortality neoplastic cell primary care setting protein-tyrosine kinase c-src small hairpin RNA tumor urinary

项目摘要

The regulation of aldosterone secretion is complex. Its biosynthesis is stimulated acutely and chronically primarily by angiotensin II (A-II) and potassium (K+) and acutely by ACTH. Excessive and autonomous production of aldosterone occurs in disorders of the adrenal zona glomerulosa (ZG) producing Primary Aldosteronism (PA). PA is the most common cause of secondary hypertension and is associated with greater risk of cardiovascular complications and death than essential hypertension of similar severity and duration. Most PA is caused by aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism (IH). The incidence of APA and IH is similar. The most recent breakthrough in understanding the pathophysiology of PA has been the discovery of somatic mutations in APAs, including those in the selectivity filter of the potassium channel KCNJ5, the sodium/potassium ATPase gene (ATP1A1), calcium ATPase, ATP2B3, CACNA1D, CACNA1H and CLCN2. The mechanism by which mutations of the sodium/potassium ATPase increases aldosterone secretion and cell proliferation for adenoma formation has been studied with contradictory results, suggesting either a loss-of-function or a gain-of-function produced by the mutations. ATP1A1 mutations occur in 25% of adenomas from white men. We will address the following hypothesis: “Somatic mutations of the ATP1A1 gene (α-subunit of the Na/K- ATPase) found in some aldosterone producing adenomas increase aldosterone biosynthesis and cell proliferation through two different mechanisms: creation of functional defects in the pump (loss-of-function), causing unregulated zona glomerulosa cell membrane depolarization, and alteration the signal transduction function of the Na/K-ATPase complex, resulting in Src and MAPK activation (gain-of-function)”. Our aims address the mechanisms by which these mutations regulate steroidogenesis and cell proliferation. 1: Elucidate the mechanisms of increased aldosterone biosynthesis and adrenal cell proliferation produced by the mutations of the human ATP1A1: L104R, V332G, del100-104, EETA963S and G99R. Do these mutations cause a gain-of-function or a loss-of-function of the ATP1A1 pump? Do different gene mutations cause a pump loss-of-function but a gain-of-function of the signaling pathways also associated with the ATP1A1. 2. Elucidate the effects of ATP1A1 and its mutations on the role of c-Src in aldo synthesis. Study the role of the sodium/calcium exchanger which is associated with the ATP1A1 on the alterations in aldo synthesis. These alternate explanations for the increase in aldo secretion will be tested in cells in which normal ATP1A1 is decreased by the shRNA and in those transduced with the various ATP1A1 mutations. These studies will elucidate mechanisms by which mutations of the ATP1A1 participate in the genesis of the hyperaldosteronism and adenoma formation and may help explain other causes of inappropriate aldo synthesis, thus lead to the development of more specific treatments than the mineralocorticoid receptor antagonists.

醛固酮分泌的调节是复杂的。它的生物合成主要受到血管紧张素II （A-II）和钾（K+）的急性和慢性刺激，以及ACTH的急性刺激。醛固酮的过度和自主生产发生在原发性醛固酮增多症（PA）的肾小球肾上腺带（ZG）紊乱。PA是继发性高血压的最常见原因，与同等严重程度和持续时间的原发性高血压相比，其心血管并发症和死亡风险更高。大多数PA是由醛固酮生成腺瘤（APA）和特发性醛固酮增多症（IH）引起的。APA和IH的发病率相似。在了解PA病理生理方面的最新突破是发现了APAs的体细胞突变，包括钾通道KCNJ5的选择性过滤器，钠/钾atp酶基因（ATP1A1），钙atp酶，ATP2B3, CACNA1D， CACNA1H和CLCN2。钠/钾atp酶突变增加醛固酮分泌和腺瘤形成的细胞增殖的机制已被研究，结果相互矛盾，表明突变可能导致功能丧失或功能获得。25%的白人男性腺瘤发生ATP1A1突变。我们将解决以下假设：“在一些醛固酮产生腺瘤中发现的ATP1A1基因（Na/K- atp酶的α-亚基）的体细胞突变通过两种不同的机制增加醛固酮的生物合成和细胞增殖：在泵中产生功能缺陷（功能丧失），导致不受调节的肾小球带细胞膜去极化，并改变Na/ k - atp酶复合物的信号转导功能，导致Src和MAPK激活（功能获得）”。我们的目标是解决这些突变调节类固醇生成和细胞增殖的机制。1：阐明人ATP1A1: L104R、V332G、del100-104、EETA963S和G99R突变导致醛固酮生物合成增加和肾上腺细胞增殖的机制。这些突变会导致ATP1A1泵的功能获得还是功能丧失？不同的基因突变是否会导致泵的功能丧失，但与ATP1A1相关的信号通路的功能获得。2. 阐明ATP1A1及其突变对c-Src在aldo合成中的作用的影响。研究与ATP1A1相关的钠/钙交换剂在aldo合成中的作用。这些对aldo分泌增加的解释将在正常ATP1A1被shRNA减少的细胞和被各种ATP1A1突变转导的细胞中进行测试。这些研究将阐明ATP1A1突变参与高醛固酮增多症和腺瘤形成的机制，并可能有助于解释醛固酮合成不当的其他原因，从而导致比矿皮质激素受体拮抗剂更特异性治疗的发展。