Regulation of Renal Phosphate Transport by Lipids

脂质对肾磷酸盐转运的调节

基本信息

  • 批准号:
    7390276
  • 负责人:
  • 金额:
    $ 29.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-04-01 至 2010-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Disorders of extracellular inorganic phosphate (Pi) concentration and impairment in Pi reabsorption are common clinical problems. Aging, diabetes mellitus, malignancy, alcoholism, transplantation, AIDS, and several therapeutic drugs are well known to cause or to be associated with hypophosphatemia or hyperphosphatemia, mainly by affecting renal tubular Pi transport. Disorders of phosphate metabolism have severe consequences on organ function including the cardiovascular system and bone mineralization. The kidney plays a critical role in the regulation of Pi homeostasis. The evidence to date indicates that regulation of the overall renal tubular Pi transport by dietary, hormonal, or metabolic factors occurs at the level of the proximal tubular apical brush border membrane (BBM) Na/Pi cotransport system (NaPi-IIa protein). Studies in our laboratory have determined that alterations in renal lipid composition, including cholesterol and glycosphingolipids play an important role in the regulation of renal Na/Pi cotransport activity and BBM membrane microdomains (or lipid rafts). The mechanisms how lipids modulate Na/Pi transport activity and NaPi-Iia protein expression and trafficking however are not well known and need to be elucidated. Our hypotheses are that perturbations in membrane cholesterol and glycosphingolipid composition regulate Na/Pi transport activity by coordinated cellular and molecular mechanisms that include I) modulating the formation of cholesterol and glycosphingolipid enriched lipid microdomains or lipid rafts that results in increased dynamic partitioning of the Na/Pi cotransporter protein in the lipid microdomains, II) modulating the lateral diffusion or mobile fraction and/or the clustering or aggregation and/or the conformational change of the Na/Pi transport proteins at the level of the apical membrane, and lII) modulating the vesicular trafficking of the Na/Pi transport protein, including endocytosis from and/or exocytosis to the apical membrane in response to alterations in extracellular Pi or PTH. The specific aims of this proposal are: 1) To determine if alterations in cholesterol and/or glycosphingolipid composition modulate a) the dynamics of cholesterol and glycosphingolipid enriched membrane microdomains (lipid rafts), b) the partitioning of the Na/Pi cotransporter proteins in the cholesterol and glycosphingolipid enriched membrane microdomains, and e) the function or transport activity of Na/Pi cotransporter proteins in these domains; 2) To determine if alterations in cholesterol or glycosphingolipid composition modulates a) the lateral diffusion and mobility, or b) the clustering and aggregation, or e) the conformational state of Na/Pi protein molecules; 3) To determine if alterations in cholesterol or glycosphingolipid composition modulates a) the apical membrane expression of Na/Pi protein and b) the acute trafficking of Na/Pi protein in response to alterations in extracellular Pi or PTH and c) the role of the actin cytoskeleton in regulation of NaPi trafficking.
描述(由申请人提供):细胞外无机磷酸盐(Pi)浓度紊乱和Pi重吸收受损是常见的临床问题。众所周知,衰老、糖尿病、恶性肿瘤、酒精中毒、移植、AIDS和几种治疗药物主要通过影响肾小管Pi转运引起低磷酸盐血症或高磷酸盐血症或与其相关。磷酸盐代谢障碍对器官功能,包括心血管系统和骨矿化有严重后果。肾脏在Pi稳态的调节中起着关键作用。迄今为止的证据表明,通过饮食、激素或代谢因素对整体肾小管Pi转运的调节发生在近端肾小管顶端刷状缘膜(BBM)Na/Pi共转运系统(NaPi-IIa蛋白)的水平。我们实验室的研究已经确定,肾脏脂质组成的改变,包括胆固醇和鞘糖脂在调节肾脏Na/Pi共转运活性和BBM膜微区(或脂筏)中起重要作用。然而,脂质如何调节Na/Pi转运活性和NaPi-IIa蛋白表达和运输的机制还不清楚,需要阐明。 我们的假设是膜胆固醇和鞘糖脂组成的扰动通过协调的细胞和分子机制调节Na/Pi转运活性,所述机制包括I)调节富含胆固醇和鞘糖脂的脂质微区或脂筏的形成,其导致脂质微区中Na/Pi共转运蛋白的动态分配增加,II)调节Na/Pi转运蛋白在顶膜水平的侧向扩散或移动的部分和/或聚集或聚集和/或构象变化,和包括响应于细胞外Pi或PTH的改变从顶膜的内吞和/或向顶膜的胞吐。 本提案的具体目的是:1)确定胆固醇和/或鞘糖脂组成的改变是否调节a)富含胆固醇和鞘糖脂的膜微区的动力学(脂筏),B)Na/Pi共转运蛋白在胆固醇和鞘糖脂富集的膜微结构域中的分配,和e)Na/Pi共转运蛋白在这些结构域中的功能或转运活性; 2)确定胆固醇或鞘糖脂组成的改变是否调节Na/Pi蛋白分子的a)侧向扩散和流动性,或B)聚集和聚集,或e)构象状态; 3)确定胆固醇或鞘糖脂组成的改变是否调节a)Na/Pi蛋白的顶膜表达和B)Na/Pi蛋白的急性运输Pi蛋白对细胞外Pi或PTH的改变的响应,以及c)肌动蛋白细胞骨架在NaPi运输调节中的作用。

项目成果

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MOSHE LEVI其他文献

MOSHE LEVI的其他文献

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{{ truncateString('MOSHE LEVI', 18)}}的其他基金

Role of Estrogen Related Receptors in Age Related Kidney Disease
雌激素相关受体在年龄相关性肾脏疾病中的作用
  • 批准号:
    10320972
  • 财政年份:
    2020
  • 资助金额:
    $ 29.73万
  • 项目类别:
Role of Estrogen Related Receptors in Age Related Kidney Disease
雌激素相关受体在年龄相关性肾脏疾病中的作用
  • 批准号:
    10154246
  • 财政年份:
    2020
  • 资助金额:
    $ 29.73万
  • 项目类别:
Role of Estrogen Related Receptors in Age Related Kidney Disease
雌激素相关受体在年龄相关性肾脏疾病中的作用
  • 批准号:
    10535466
  • 财政年份:
    2020
  • 资助金额:
    $ 29.73万
  • 项目类别:
Treatment of kidney disease in diabetes
糖尿病肾病的治疗
  • 批准号:
    10133461
  • 财政年份:
    2018
  • 资助金额:
    $ 29.73万
  • 项目类别:
Treatment of kidney disease in diabetes
糖尿病肾病的治疗
  • 批准号:
    9884758
  • 财政年份:
    2018
  • 资助金额:
    $ 29.73万
  • 项目类别:
Role of FXR and TGR5 in Age Related Renal Diseases
FXR 和 TGR5 在年龄相关性肾脏疾病中的作用
  • 批准号:
    8984793
  • 财政年份:
    2016
  • 资助金额:
    $ 29.73万
  • 项目类别:
Role of FXR and TGR5 in Age Related Renal Diseases
FXR 和 TGR5 在年龄相关性肾脏疾病中的作用
  • 批准号:
    9346676
  • 财政年份:
    2016
  • 资助金额:
    $ 29.73万
  • 项目类别:
Non-Invasive Evaluation of Transplant Kidney using OCT
使用 OCT 对移植肾进行无创评估
  • 批准号:
    9259961
  • 财政年份:
    2014
  • 资助金额:
    $ 29.73万
  • 项目类别:
Treatment of Kidney Disease in Diabetes and Obesity
糖尿病和肥胖症肾病的治疗
  • 批准号:
    8743204
  • 财政年份:
    2013
  • 资助金额:
    $ 29.73万
  • 项目类别:
2013 Kern Lipid Conference
2013年科恩脂质会议
  • 批准号:
    8597637
  • 财政年份:
    2013
  • 资助金额:
    $ 29.73万
  • 项目类别:

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