Functional Relevance of CFTR Trafficking in Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
基本信息
- 批准号:8316450
- 负责人:
- 金额:$ 5.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsActinsAcuteAgonistAnimal ModelApicalBicarbonatesBindingBinding SitesBiochemicalBiologicalBiological AssayCell membraneCell modelCell surfaceCellsChloride ChannelsChloride IonChloridesCholera ToxinCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic GMPCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDiarrheaDiseaseDuodenumElectrophysiology (science)EndocytosisEnterocytesEnterotoxinsExocytosisFluids and SecretionsFunctional disorderGoalsHealthHeatingImmunoprecipitationIntestinal DiseasesIntestinesInvestigationLeadLinkMediatingMembraneMotorMovementMusMutationOrganellesPathogenesisPathway interactionsPerfusionPhosphorylationPhysiologicalPhysiologyRNA InterferenceRattusRegulationRoleSecond Messenger SystemsSignal TransductionSite-Directed MutagenesisSmall Interfering RNASpecificitySurfaceTissuesTransgenic MiceTransgenic OrganismsVesicleapical membranebasein vivoin vivo Modelinsightjejunummeetingsmutantmyosin VIsecond messengertrafficking
项目摘要
DESCRIPTION (provided by applicant): In cystic fibrosis (CF), mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are associated with defective cAMP and acid-stimulated duodenal bicarbonate secretion, and defective cAMP and cGMP-activated fluid secretion in the intestine. On the other hand, increased activation of CFTR by cAMP and cGMP agonists elicit massive fluid secretion that result in secretory diarrhea. But the mechanisms responsible for increased or decreased activation of CFTR on the apical plasma membrane under physiological conditions in the intestine are unknown. Protein kinase A and G (PKA, PKG) phosphorylation is accepted as central to CFTR regulation. But this dogma assumes that CFTR is confined to the apical plasma membrane. We hypothesize that under physiological conditions in the intetsine, cell and region specific trafficking regulate the number and function of CFTR channels on the cell surface and contribute to disease pathogenesis. This hypothesis is supported by the following observations: (1) CFTR expression is cell and region-specific in the intestine (2) more than 50% of CFTR is in intracellular organelles in native enterocytes and supports constituitive and regulated trafficking in vivo (3) PKA and PKG regulate CFTR trafficking to the cell surface and fluid secretion in a cell and region specific manner in the intestine (4) in the duodenum, cAMP and luminal acid regulate CFTR trafficking and bicarbonate secretion (5) the endocytosis of CFTR from the apical plasma membrane in the intestine of transgenic mice lacking expression of the actin-binding motor myosin VI (Myo6 (sv/sv))is markedly defective, leads to its accumulation on the cell surface and increased CFTR-activated fluid secretion elicited by the cGMP- agonist Heat Stable Enterotoxin in vivo. Over the next five years, we propose to expand these observations and further elucidate the biological relevance of region and cell-specificity of CFTR trafficking, the role of luminal acid in regulating CFTR trafficking and function in the duodenum and the mechanism by which myosin VI regulates CFTR trafficking. We plan an integrative approach that incorporates state of the art cell biological structural, biochemical, and immunological studies including RNA silencing and in vivo perfusion and electrophysiology. These approaches, in conjunction with in vivo models of rat, and transgenic Myo6 (sv/sv) mouse intestine, polarized secretory and absorptive intestinal cells expressing endogenous CFTR and WT (wild type), DF508 and N287Y mutant CFTR-expressing cells will facilitate a comprehensive investigation to meet the defined goals of this proposal. PUBLIC HEALTH RELEVANCE In cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator CFTR chloride channel fails to reach the plasma membrane of cells and in secretory diarrhea, CFTR function on the membrane of intestinal cells is increased. But the mechanisms that lead to CF or secretory diarrhea are unknown. This proposal seeks to understand the mechanisms that regulate CFTR movement into to the membrane under physiological conditions in the intestine in order to elucidate how dysfunction of CFTR leads to either CF or secretory diarrhea.
描述(由申请人提供):在囊性纤维化(CF)中,囊性纤维化跨膜电导调节剂(CFTR)氯化物通道中的突变与cAMP和酸刺激的十二指肠碳酸氢苯甲酸盐分泌有缺陷以及有缺陷的CAMP和CGMP活化的流体分泌有关肠。另一方面,CAMP和CGMP激动剂对CFTR的激活增加引起大规模的液体分泌,从而导致分泌性腹泻。但是,在肠道生理条件下,导致CFTR激活增加或减少的机制尚不清楚。蛋白激酶A和G(PKA,PKG)磷酸化被接受为CFTR调节的核心。但是该教条假设CFTR仅限于顶端质膜。我们假设在胸他,细胞和区域特定运输的生理条件下,调节CFTR通道在细胞表面的数量和功能,并导致疾病发病机理。该假设得到以下观察结果的支持:(1)CFTR表达是细胞,在肠道(2)中特定区域特异性(2)在天然肠上皮细胞的细胞内细胞器中,有50%以上的CFTR在体内的组成和调节的运输(3)中(3) PKA和PKG在十二指肠,cAMP和Luminal Acid中以细胞和区域特异性方式调节CFTR运输到细胞表面,并以细胞和区域的特定方式调节CFTR的CFTR运输和碳酸氢盐分泌(5)CFTR的CFTR来自Apical的内吞作用(5)缺乏肌动蛋白结合运动肌球蛋白VI表达的转基因小鼠肠道中的质膜明显有缺陷,导致其在细胞表面积聚并增加了CFTR激活的流体分泌,由CGMP-P-P-P-P-PRID分泌产生。激动剂热稳定的体内肠毒素。在接下来的五年中,我们建议扩大这些观察结果,并进一步阐明CFTR运输区域和细胞特异性的生物学相关性,Luminal Acid在调节DuodoDeNum中调节CFTR运输和功能方面的作用以及肌球蛋白VI调节的机制CFTR贩运。我们计划了一种综合方法,该方法结合了艺术细胞生物学结构,生化和免疫学研究,包括RNA沉默和体内灌注和电生理学。这些方法与大鼠体内模型以及转基因Myo6(SV/SV)小鼠肠,表达内源性CFTR和WT(野生型),DF508和N287Y突变体CFTR CFTR的细胞表达内源性CFTR和WT(野生型)的极化分泌和吸收性肠道细胞将有助于促进A全面的调查以满足该提案的明确目标。公共卫生在囊性纤维化(CF)中,囊性纤维化跨膜电导调节剂CFTR氯化物通道无法达到细胞的质膜和分泌腹泻,CFTR在肠细胞膜上的CFTR功能增加了。但是导致CF或分泌性腹泻的机制尚不清楚。该提案试图了解在肠道中的生理条件下将CFTR运动转化为膜的机制,以阐明CFTR功能障碍如何导致CF或分泌性腹泻。
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)
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Nadia A. Ameen其他文献
Nadia A. Ameen的其他文献
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{{ truncateString('Nadia A. Ameen', 18)}}的其他基金
Functional Relevance of CFTR Trafficking in Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
- 批准号:
7913843 - 财政年份:2009
- 资助金额:
$ 5.32万 - 项目类别:
Glucocorticoid and SGK1 regulation of CFTR in the intestine: role in diarrhea
糖皮质激素和 SGK1 对肠道 CFTR 的调节:在腹泻中的作用
- 批准号:
10293338 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Glucocorticoid and SGK1 Regulation of CFTR in the Intestine: Role in Diarrhea
糖皮质激素和 SGK1 对肠道 CFTR 的调节:在腹泻中的作用
- 批准号:
10162075 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Glucocorticoid and SGK1 regulation of CFTR in the intestine: role in diarrhea
糖皮质激素和 SGK1 对肠道 CFTR 的调节:在腹泻中的作用
- 批准号:
10681492 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Functional Relevance of CFTR Trafficking in Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
- 批准号:
8245108 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Functional Relevance of CFTR Trafficking In Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
- 批准号:
8587384 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Functional Relevance of CFTR Trafficking In Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
- 批准号:
8691793 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Glucocorticoid and SGK1 regulation of CFTR in the intestine: role in diarrhea
糖皮质激素和 SGK1 对肠道 CFTR 的调节:在腹泻中的作用
- 批准号:
10475278 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Functional Relevance of CFTR Trafficking in Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
- 批准号:
7591240 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
Functional Relevance of CFTR Trafficking in Vivo to Intestinal Disease
CFTR 体内贩运与肠道疾病的功能相关性
- 批准号:
8055437 - 财政年份:2008
- 资助金额:
$ 5.32万 - 项目类别:
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