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The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis

The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
ENaC 的 ATP 依赖性抑制参与 ARPKD 囊肿发生
批准号:
10419229
负责人:
Daria Ilatovskaya
金额:
$2.11万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-02-15 至 2022-01-31

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中文摘要
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英文摘要
PROJECT SUMMARY Polycystic kidney diseases (PKD) are a group of inherited nephropathies characterized by the formation of fluid- filled cysts along the nephron. Autosomal Recessive form of PKD (ARPKD) has an incidence of 1 in 20,000 live births; infants with this disease that survive beyond the perinatal period develop chronic renal failure by adolescence and eventually require kidney transplantation. This proposal focuses on the sodium transport regulation in the renal collecting ducts in ARPKD and potential means of pharmacological intervention with the cysts’ progression. Specifically, we have determined that Epithelial Sodium Channels (ENaCs), which are expressed in the collecting ducts and represent the rate-limiting step of sodium reabsorption in this nephron segment, are involved into the process of cystogenesis in the ARPKD setting. Our preliminary data indicate that ENaC expression and activity are significantly lower in the cystic epithelial cells of a rat model of ARPKD, as assessed with immunohistochemistry and single channel analysis in isolated cysts; furthermore, chronic administration of the ENaC-specific inhibitor, benzamil, aggravated cyst formation. Using a novel enzymatic microbiosensors approach we established that concentration of adenosine triphosphate (ATP) was significantly higher in PCK rat cortical cysts compared to control rats. ATP was shown to inhibit ENaC via signaling cascades initiated by binding to its receptors. Therefore, we hypothesized here that accumulation of excessive levels of ATP in the lumen of the dilated collecting ducts affects specific purinergic receptors in the cystic cells and results in ENaC inhibition; this suppresses normal sodium reabsorption in these collecting ducts, and promotes fluid accumulation and cysts’ expansion. The integrative experimental approach used in this study will include single nephron electrophysiology, in vivo animal studies, genetics, biochemistry, biosensors amperometry and confocal microscopy and will address the clinically relevant problem of cyst expansion in ARPKD. Specifically, this proposal will identify the receptors involved in the purinergic signaling in the cystic cells, and study the relevance of ATP signaling to sodium reabsorption dependent on sodium content in the diet. This proposal will address the following specific aims: 1. Determine the relationship between ENaC activity and cystogenesis in ARPKD; 2. Elucidate the cellular and molecular mechanism by which excessive levels of ATP modulate sodium transport, promoting cyst growth; and 3. Explore if P2 receptor agonists/antagonists and suppression of the ATP levels can affect cystogenesis.
期刊论文(8)
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会议论文
DOI: 10.1177/1470320316653858
发表时间: 2016-07
期刊: Journal of the renin-angiotensin-aldosterone system : JRAAS
影响因子: --
作者: [Pavlov TS, Levchenko V, Ilatovskaya DV, Moreno C, Staruschenko A]
通讯作者: Staruschenko A
DOI: 10.1016/j.lfs.2015.12.022
发表时间: 2016-08-15
期刊: Life sciences
影响因子: 6.1
作者: [Palygin O, Miller B, Ilatovskaya DV, Sorokin A, Staruschenko A]
通讯作者: Staruschenko A
DOI: 10.14814/phy2.12950
发表时间: 2016-09
期刊: Physiological reports
影响因子: 2.5
作者: [Blass G, Levchenko V, Ilatovskaya DV, Staruschenko A]
通讯作者: Staruschenko A
DOI: 10.3389/fphys.2021.693130
发表时间: 2021
期刊: Frontiers in physiology
影响因子: 4
作者: [Vasileva VY, Sultanova RF, Sudarikova AV, Ilatovskaya DV]
通讯作者: Ilatovskaya DV
Improving awareness of women with hypertension: ROAR (Rural, Obese, At Risk) Career Enhancement Core
  • 批准号:
    10714535
  • 项目类别:
  • 资助金额:
    $45.11万
  • 财政年份:
    2023
  • 负责人:
    Daria Ilatovskaya
  • 依托单位:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
  • 批准号:
    10676800
  • 项目类别:
  • 资助金额:
    $52.54万
  • 财政年份:
    2020
  • 负责人:
    Daria Ilatovskaya
  • 依托单位:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
  • 批准号:
    10442162
  • 项目类别:
  • 资助金额:
    $56.94万
  • 财政年份:
    2020
  • 负责人:
    Daria Ilatovskaya
  • 依托单位:
Mitochondria-Mediated Effects and Therapeutic Potential of Atrial Natriuretic Peptide in Salt-Sensitive Hypertension Diversity Supplement
国内基金
海外基金
SIRT4介导的ATP5β乙酰化修饰在血管平滑肌细胞衰老和腹主动脉瘤中的作用和机制研究
  • 批准号:
    2026JJ50331
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2026
  • 负责人:
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  • 依托单位:
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    2026JJ81265
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2026
  • 负责人:
    尹翔安
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小分子化合物T-2307及其类似物通过PG-PMF-ATP通路抗MRSA感染的分子机制及应用研究
ATP13A2介导HDAC6溶酶体定位在抑郁模型中的作用机制研究
  • 批准号:
    JCZRQNB202600165
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2026
  • 负责人:
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