Regulation of Aldosterone Production in the Adrenal

肾上腺醛固酮生成的调节

基本信息

  • 批准号:
    8442673
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-10-01 至 2016-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Aldosterone is the main mineralocorticoid hormone involved in maintaining fluid and electrolyte (sodium) balance in the human body. However, abnormalities in aldosterone production and secretion from the adrenal gland result in and/or exacerbate several human diseases including high blood pressure and congestive heart failure. These disorders are prevalent in the veteran population, with nearly 3.5 million veterans diagnosed with hypertension and approximately 10% of these with congestive heart failure. Similarly, many veterans are overweight or obese, with the attendant disorders associated with excess weight, including hypertension. The mechanism by which excess weight causes hypertension is unclear; however, some studies have suggested a link with increased aldosterone levels. Our recent novel results demonstrate that physiological concentrations of very-low-density lipoprotein (VLDL) stimulate aldosterone production in multiple zona glomerulosa cell models in vitro. This result suggests a possible mechanism by which obesity, which is associated with elevated VLDL levels (dyslipidemia), can result in hypertension resulting, at least in part, from inappropriate aldosterone secretion. To increase our understanding of the mechanisms underlying VLDL-induced aldosterone production, three specific aims are proposed in this study: (1) test the hypothesis that physiological and pathophysiological VLDL concentrations will enhance the response to other physiological stimulators of aldosterone production and determine the signaling mechanisms involved in the stimulatory action of VLDL, (2) test the hypothesis that a lipid component of VLDL elicits aldosterone secretion and define this active component, and (3) test the hypothesis that ablation of the gene encoding phospholipase D2 (PLD2), an important signal mediating aldosterone production in vitro, also regulates aldosterone levels in vivo, basally and with elevated VLDL levels related to diet-induced obesity. These hypotheses will be tested by monitoring aldosterone production in glomerulosa cell models treated with various concentrations of VLDL and other aldosterone agonists. In addition, the signal transduction mechanisms utilized by VLDL will be defined using overexpression and RNA interference-mediated knock down strategies to influence the levels of signaling molecules followed by a determination of the effect of these manipulations on VLDL-induced aldosterone production. Pretreatment to denature/degrade the protein and extraction of the lipids comprising VLDL, as well as lipidomics to identify VLDL lipid components, will be used to determine the agent in VLDL responsible for stimulating aldosterone production. The role of this VLDL component will be verified in studies determining the aldosterone stimulatory effect of VLDL pretreated using enrichment and depletion strategies to alter levels of the identified active agent. In vivo a PLD2 knockout mouse model will be used to determine the effects of the loss of PLD2 on aldosterone levels and aldosterone synthase (CYP11B2) expression in the adrenal basally and upon chronic angiotensin II infusion or with diet-induced obesity. The proposed studies examining the ability of VLDL to modulate aldosterone production will expand our knowledge of the role of obesity-increased VLDL levels in the development of hypertension in obese and/or lean individuals, as well as the possible involvement of abnormalities in the VLDL-activated signals in hypertension in these individuals.
描述(由申请人提供): 醛固酮是维持人体内液体和电解质(钠)平衡的主要矿物质皮质激素。然而,肾上腺产生和分泌醛固酮的异常会导致和/或加剧一些人类疾病,包括高血压和充血性心力衰竭。这些疾病在退伍军人中很普遍,近350万退伍军人被诊断患有高血压,其中约10%患有充血性心力衰竭。同样,许多退伍军人超重或肥胖,伴随而来的与超重相关的疾病,包括高血压。超重导致高血压的机制尚不清楚;然而,一些研究表明,这与醛固酮水平升高有关。我们最近的新结果表明,生理浓度的极低密度脂蛋白(VLDL)在体外刺激多个肾小球带细胞模型中的醛固酮产生。这一结果表明,与极低密度脂蛋白水平升高(血脂异常)相关的肥胖可能导致高血压,至少部分原因是不适当的醛固酮分泌。为了加深我们对极低密度脂蛋白诱导的醛固酮产生机制的了解,本研究提出了三个具体的目标:(1)检验生理和病理生理学的极低密度脂蛋白浓度将增强对其他醛固酮产生的生理刺激物的反应的假说,并确定参与极低密度脂蛋白刺激作用的信号机制;(2)检验极低密度脂蛋白的脂类成分诱导醛固酮分泌的假说并确定其活性成分;(3)检验假说:切割编码磷脂酶D2(PLD2)的基因也调节体内、基础和与饮食诱导的肥胖相关的极低密度脂蛋白水平升高的醛固酮水平。这些假说将通过监测不同浓度的极低密度脂蛋白和其他醛固酮激动剂处理的肾小球细胞模型中的醛固酮产生来检验。此外,VLDL所利用的信号转导机制将通过过度表达和RNA干扰介导的击倒策略来确定,以影响信号分子的水平,然后确定这些操作对VLDL诱导的醛固酮产生的影响。将使用变性/降解蛋白质和提取组成极低密度脂蛋白的脂质的预处理,以及鉴定极低密度脂蛋白脂质成分的脂质组学,以确定极低密度脂蛋白中负责刺激醛固酮产生的因素。这一极低密度脂蛋白成分的作用将在确定极低密度脂蛋白的醛固酮刺激作用的研究中得到验证,该研究使用浓缩和耗竭策略来改变已确定的活性物质的水平。在体内,PLD2基因敲除小鼠模型将被用来确定PLD2基因缺失对基础和慢性血管紧张素II注射或饮食诱导肥胖时肾上腺醛固酮水平和醛固酮合成酶(CYP11B2)表达的影响。拟议中的研究将探讨极低密度脂蛋白调节醛固酮生成的能力,这将扩大我们对肥胖引起的极低密度脂蛋白水平升高在肥胖和/或瘦人高血压发病中的作用的认识,以及极低密度脂蛋白激活信号异常在这些人高血压中的可能参与。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Wendy B Bollag其他文献

Association of psoriasis and stroke in end-stage renal disease patients.
终末期肾病患者牛皮癣和中风的关联。
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    N. Siddiquee;J. Waller;S. Baer;Azeem A. Mohammed;S. Tran;S. Padala;Lufei Young;M. Kheda;Wendy B Bollag
  • 通讯作者:
    Wendy B Bollag

Wendy B Bollag的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Wendy B Bollag', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10373069
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10618156
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
The Aquaporin-3/Phospholipase D2 Signaling Pathway in Corneal Wound Healing
角膜伤口愈合中的 Aquaporin-3/磷脂酶 D2 信号通路
  • 批准号:
    10664930
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
  • 批准号:
    10407548
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
  • 批准号:
    9982017
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
  • 批准号:
    10163771
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
The Aquaporin-3/Phospholipase D2 Signaling Pathway in Corneal Wound Healing
角膜伤口愈合中的 Aquaporin-3/磷脂酶 D2 信号通路
  • 批准号:
    10201519
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
The Aquaporin-3/Phospholipase D2 Signaling Pathway in Corneal Wound Healing
角膜伤口愈合中的 Aquaporin-3/磷脂酶 D2 信号通路
  • 批准号:
    10016063
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
  • 批准号:
    10624835
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Phosphatidylglycerol as a Therapy for Corneal Injury
磷脂酰甘油治疗角膜损伤
  • 批准号:
    10179401
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
  • 批准号:
    484000
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了