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，其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，肾上腺肾小球带 (ZG) 疾病会急性和自主地产生醛固酮。）产生的原发性醛固酮增多症（PA）是继发性高血压的最常见原因，与原发性高血压相比，与心血管并发症和死亡的风险更大。大多数 PA 是由产生醛固酮的腺瘤 (APA) 和特发性醛固酮增多症 (IH) 引起的。APA 和 IH 的发病率相似。了解 PA 病理生理学的最新突破是体细胞突变的发现。 APA 中，包括钾通道 KCNJ5 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细胞增殖以形成腺瘤的机制已得到相互矛盾的结果，表明功能丧失或功能获得。 ATP1A1 突变发生在 25% 的白人腺瘤中，我们将提出以下假设：“体细胞突变。在一些产生醛固酮的腺瘤中发现的 ATP1A1 基因（Na/K-ATP 酶的 α 亚基）通过两种不同的机制增加醛固酮生物合成和细胞增殖：在泵中产生功能缺陷（功能丧失），导致球状带不受调节细胞膜去极化，改变 Na/K-ATPase 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：阐明人类 ATP1A1：L104R、V332G 突变引起的醛固酮生物合成增加和肾上腺细胞增殖的机制。 del100-104、EETA963S 和 G99R 这些突变会导致功能获得还是功能丧失。 ATP1A1 泵？不同的基因突变会导致泵功能丧失，但也会导致与 ATP1A1 相关的信号通路功能获得吗？ 2. 阐明 ATP1A1 及其突变对 c-Src 在细胞中的作用的影响。研究与 ATP1A1 相关的钠/钙交换器对 ALDO 合成变化的作用，将在细胞中测试这些对 ALDO 分泌增加的替代解释。这些研究将阐明 ATP1A1 突变参与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。，从而导致比盐皮质激素受体拮抗剂更具体的治疗方法的开发。