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:10210433
- 负责人:
- 金额:$ 31.88万
- 依托单位:
- 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:
- 关键词:ATP phosphohydrolaseATP1A1 geneAcuteAddressAdrenal Gland DiseasesAdrenal GlandsAdultAffectAgeAgingAldosteroneAnabolismAngiotensin IIBilateralCa(2+)-Transporting ATPaseCalciumCalcium ChannelCardiovascular DiseasesCardiovascular systemCell ProliferationCell membraneCellsCessation of lifeChloride ChannelsChronicClinicComplexCorticotropinCoupledDefectDevelopmentEnzymesEssential HypertensionFunctional disorderGene MutationGenesGrowthHumanHyperaldosteronismHyperplasiaHypertensionHypertrophyIncidenceIndividualInflammationKidneyLeadMAP Kinase GeneMembraneMineralocorticoid ReceptorMonoclonal AntibodiesMorbidity - disease rateMutationNa(+)-K(+)-Exchanging ATPaseOralOuabainPathway interactionsPatientsPatternPeptidesPlasmaPlayPotassiumPotassium ChannelProductionPumpRegulationReportingRoleSRC geneSecondary HypertensionSeveritiesSignal PathwaySignal TransductionSignal Transduction AlterationSodium ChlorideSodium-Calcium ExchangerSomatic MutationSteroid biosynthesisTestingZona Glomerulosaadenomabeta catenincardiovascular risk factorcellular transductiongain of functionhigh riskinward rectifier potassium channelloss of functionloss of function mutationlow renin hypertensionmenmortalityneoplastic cellprimary care settingprotein-tyrosine kinase c-srcsmall hairpin RNAtumorurinary
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。它的生物合成主要由血管紧张素II(A-II)和钾(K+)以及ACTH急性和慢性刺激。醛固酮的过度和自主产生发生在产生原发性醛固酮增多症(PA)的肾上腺肾小球性疾病(ZG)中。PA是继发性高血压的最常见原因,与严重程度和持续时间相似的原发性高血压相比,PA与心血管并发症和死亡的风险更高相关。大多数PA是由醛固酮腺瘤(阿帕)和特发性醛固酮增多症(IH)引起的。阿帕和IH的发病率相似。在了解PA的病理生理学方面的最新突破是发现了APA的体细胞突变,包括钾通道KCNJ 5、钠/钾ATP酶基因(ATP 1A 1)、钙ATP酶、ATP 2B 3、CACNA 1D、CACNA 1H和CLCN 2的选择性过滤器中的突变。已经研究了钠/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,结果相互矛盾,表明突变产生的功能丧失或功能获得。25%的白色男性腺瘤中存在ATP 1A 1突变。我们将讨论以下假设:“ATP 1A 1基因的体细胞突变在一些醛固酮生成腺瘤中发现的Na/K-ATP酶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),引起不受调节的肾小球细胞膜去极化,并改变Na/K-ATP酶复合物的信号转导功能,导致Src和MAPK活化(功能获得性)"。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。一曰:阐明人ATP 1A 1:L104 R、V332 G、del 100 -104、EETA 963 S和G99 R突变导致醛固酮生物合成增加和肾上腺细胞增殖的机制。这些突变是否会导致ATP 1A 1泵的功能获得或功能丧失?不同的基因突变是否会导致泵功能丧失,但信号通路的功能获得也与ATP 1A 1相关。2.阐明ATP 1A 1及其突变对c-Src在醛合成中作用的影响。研究与ATP 1A 1相关的钠/钙交换体在醛合成改变中的作用。这些aldo分泌增加的替代解释将在正常ATP 1A 1被shRNA减少的细胞中以及用各种ATP 1A 1突变转导的细胞中进行测试。这些研究将阐明ATP 1A 1突变参与醛固酮增多症和腺瘤形成的机制,并可能有助于解释不适当的aldo合成的其他原因,从而导致比盐皮质激素受体拮抗剂更特异性的治疗方法的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Celso Enrique Gomez-Sanchez其他文献
Celso Enrique Gomez-Sanchez的其他文献
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{{ truncateString('Celso Enrique Gomez-Sanchez', 18)}}的其他基金
Regulation of Mineralocorticoid Receptor Action
盐皮质激素受体作用的调节
- 批准号:
10553631 - 财政年份:2020
- 资助金额:
$ 31.88万 - 项目类别:
Regulation of Mineralocorticoid Receptor Action
盐皮质激素受体作用的调节
- 批准号:
10293532 - 财政年份:2020
- 资助金额:
$ 31.88万 - 项目类别:
Regulation of Mineralocorticoid Receptor Action
盐皮质激素受体作用的调节
- 批准号:
10436926 - 财政年份:2020
- 资助金额:
$ 31.88万 - 项目类别:
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
- 批准号:
9981536 - 财政年份:2019
- 资助金额:
$ 31.88万 - 项目类别:
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
- 批准号:
10447775 - 财政年份:2019
- 资助金额:
$ 31.88万 - 项目类别:
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
- 批准号:
9813129 - 财政年份:2019
- 资助金额:
$ 31.88万 - 项目类别:
Regulation of the late-pathway of aldosterone biosynthesis
醛固酮生物合成后期途径的调节
- 批准号:
8254384 - 财政年份:2011
- 资助金额:
$ 31.88万 - 项目类别:
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