Role of Na+/H+ exchanger in diabetic diarrhea
Na /H 交换剂在糖尿病腹泻中的作用
基本信息
- 批准号:10516034
- 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:2019
- 资助国家:美国
- 起止时间:2019-10-01 至 2024-09-30
- 项目状态:已结题
- 来源:
- 关键词:Adenosine MonophosphateAdverse effectsAffectAntidiabetic DrugsBicarbonatesBifidobacteriumBile AcidsBiological ProductsButyratesCaringCell modelColonComplications of Diabetes MellitusCoupledDataDiabetes MellitusDiarrheaDrug PrescriptionsElectrolytesEpithelial CellsExocytosisExperimental ModelsFRAP1 geneFreedomFunctional disorderGastrointestinal MotilityGastrointestinal TransitGenomicsGoalsGrowthHealthHealth ServicesHumanHydrogenIn VitroIncidenceInflammatoryIntestinesIonsLinkLiquid substanceMalabsorption SyndromesMediatingMediatorMessenger RNAMetforminMilitary PersonnelMusNatureNon-Insulin-Dependent Diabetes MellitusObesityOverweightPRKCA genePatientsPharmaceutical PreparationsPhospholipidsPhosphotransferasesPreclinical TestingProbioticsRefractoryRegulationReportingResearch DesignRoleSchemeSeveritiesSignal PathwaySodiumSoldierTestingTimeTissuesType 2 diabeticUbiquitinationUnited StatesUnited States Department of Veterans AffairsVeteransVolatile Fatty Acidsabsorptionclinically relevantclinically significantdb/db mousediabeticdiabetic patientefficacy testingexperiencegastrointestinalglycemic controlhumanized mouseimprovedin vivointestinal epitheliumlysophosphatidic acidmouse modelnew therapeutic targetnon-genomicoperationpharmacologicpreclinical studypreventprotein protein interactionservice membertargeted treatmenttype I diabeticubiquitin-protein ligase
项目摘要
Diarrhea is one of the most frequent complaints in deployed military personnel from the United States and has
significant adverse effects on the health of service members. It was reported that 76.8 % of soldiers in Operation
Iraqi Freedom and Operation Enduring Freedom experienced diarrhea. Diabetes is becoming an increasing
health concern for veterans, with one in four veterans receiving care from the Department of Veterans Affairs
has diabetes. A common troublesome gastrointestinal complication of diabetes is diarrhea. Diabetic diarrhea
attains clinical significance because of its severity and refractory nature. The overall incidence of diabetic
diarrhea can reach as high as 22%. Although diarrhea is less frequent in type 2 diabetic mellitus (T2DM), the
frequent cause of diarrhea in T2DM is associated with drugs, including metformin, which is commonly used for
glycemic control in T2DM. Clinical Relevance to the Department of Veterans Affair is that with more than 70% of
patients in VA facilities being overweight or obese, T2DM is a major health concern. Yet the underlying cause of
diarrhea in T2DM has not been studied and there is a need to improve treatment for diabetic diarrhea. Diarrhea
is caused by altered intestinal transport of electrolytes and fluid, but the link between the aberrant electrolyte
transport and diabetic diarrhea is not established. The major Na+ absorptive mechanism in the intestine is
electroneutral NaCl absorption mediated by the Na+/H+ exchanger 3 (NHE3). Inhibition of NHE3 is associated
with both enterotoxigenic and inflammatory diarrhea. Our recent study of type 1 diabetic mellitus (T1DM) showed
that NHE3 expression is downregulated in T1DM humans and mice, which helped to identify a specific ion
transporter as a cause of diabetic diarrhea for the first time. Preliminary studies have demonstrated that NHE3
expression is decreased in human diabetic tissues and db/db mice, a mouse model for T2DM. Additionally, we
have compelling evidence that metformin, a widely prescribed drug to treat T2DM, inhibits NHE3, suggesting
NHE3 dysfunction is associated with frequent diarrhea caused by metformin. Adenosine monophosphate kinase
(AMPK) is a major effector of anti-diabetic metformin, and activation of AMPK causes NHE3 inhibition,
suggesting the critical role of AMPK in NHE3 regulation by metformin. The objective of the proposed study is
determine the impact of decreased NHE3 expression and activity in diabetic diarrhea, in particular T2DM. The
central hypothesis of this proposed study is that inhibition of NHE3 by elevated PKCα is a major cause of NHE3
inhibition in T2DM, and activation of AMPK by anti-diabetic drugs such as metformin further inhibits NHE3,
contributing to diarrhea in some patients. The proposed studies designed to test this hypothesis will establish a
new paradigm that diabetic diarrhea is caused by aberrant regulation of sodium and fluid transport by NHE3. We
propose to test the hypothesis that PKCα is a major cause of reduced NHE3 activity and fluid absorption in T2DM
mice using intestinal epithelial cells and experimental models of T2DM (Aim 1). We propose to determine that
AMPK inhibits NHE3 in vitro and in vivo. We will determine the underlying mechanism of NHE3 inhibition by
AMPK by investigating signal pathways responsible NHE3 inhibition. We also plan to determine whether AMPK
activation by metformin mediates NHE3 inhibition via ubiquitination of NHE3 by using humanized mice (Aim 2).
As a pre-clinical test to improve the treatment for diabetic diarrhea, we will test the efficacy of a biologically
occurring phospholipid, lysophosphatidic acid, and probiotics in mitigating the inhibition of NHE3 (Aim 3).
腹泻是来自美国的部署军事人员最常见的抱怨之一,并已
对服役人员的健康产生重大不利影响。据报道,76.8%的士兵在行动中
伊拉克自由和持久自由行动经历了腹泻。糖尿病正在成为一种日益严重的
对退伍军人的健康关注,四分之一的退伍军人得到退伍军人事务部的照顾
患有糖尿病。糖尿病常见的令人头疼的胃肠道并发症是腹泻。糖尿病腹泻
因其严重性和难治性而具有临床意义。糖尿病的总发病率
腹泻的比例可能高达22%。虽然2型糖尿病(T2 DM)患者腹泻的发生率较低,但
T2 DM患者腹泻的常见原因与药物有关,包括二甲双胍,它通常用于
2型糖尿病患者的血糖控制。与退伍军人事务部的临床相关性是,超过70%的
退伍军人管理局的患者超重或肥胖,T2 DM是一个主要的健康问题。然而,造成这种情况的根本原因
T2 DM的腹泻尚未被研究,因此有必要改进糖尿病腹泻的治疗。腹泻
是由电解质和液体的肠道运输改变引起的,但异常的电解质之间的联系
运输和糖尿病腹泻没有得到证实。肠道对Na+的主要吸收机制是
Na+/H+交换器3(NHE3)介导的电中性盐吸收。对NHE3的抑制与
同时伴有肠毒素和炎症性腹泻。我们最近对1型糖尿病(T1 DM)的研究表明
在T1 DM患者和小鼠中,NHE3的表达下调,这有助于识别特定的离子
转运蛋白首次被认为是糖尿病腹泻的原因。初步研究表明,NHE3
在人类糖尿病组织和T2 DM小鼠模型db/db小鼠中表达减少。此外,我们
有令人信服的证据表明,治疗T2 DM的广泛处方药二甲双胍抑制NHE3,这表明
NHE3功能障碍与二甲双胍引起的频繁腹泻有关。一磷酸腺苷激酶
AMPK是抗糖尿病药物二甲双胍的主要效应者,AMPK的激活导致NHE3抑制,
提示AMPK在二甲双胍对NHE3的调控中起关键作用。拟议研究的目标是
确定NHE3表达和活性降低在糖尿病腹泻,特别是T2 DM中的影响。这个
这项研究的中心假设是,PKCα升高对NHE3的抑制是NHE3的主要原因
对T2 DM的抑制和抗糖尿病药物如二甲双胍对AMPK的激活进一步抑制NHE3,
导致一些患者腹泻。旨在检验这一假设的拟议研究将建立一个
新的范式认为,糖尿病腹泻是由NHE3对钠和液体运输的异常调节引起的。我们
建议检验PKCα是T2 DM患者NHE3活性降低和液体吸收减少的主要原因这一假设
使用肠上皮细胞的小鼠和T2 DM的实验模型(目标1)。我们建议确定
AMPK在体内外对NHE3均有抑制作用。我们将通过以下方法确定NHE3抑制的潜在机制
AMPK通过研究导致NHE3抑制的信号通路。我们还计划确定AMPK是否
在人源化小鼠中,二甲双胍激活通过泛素化NHE3介导对NHE3的抑制(目标2)。
作为一项改善糖尿病腹泻治疗的临床前试验,我们将从生物学角度测试一种
出现磷脂、溶血磷脂酸和益生菌以减轻对NHE3的抑制(目标3)。
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 }}
Changhyon Chris Yun其他文献
Changhyon Chris Yun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('Changhyon Chris Yun', 18)}}的其他基金
The function of lysophosphatidic acid receptor LPA5R in intestinal inflammation and epithelial damage
溶血磷脂酸受体LPA5R在肠道炎症和上皮损伤中的作用
- 批准号:
10163842 - 财政年份:2018
- 资助金额:
-- - 项目类别:
The function of lysophosphatidic acid receptor LPA5R in intestinal inflammation and epithelial damage
溶血磷脂酸受体LPA5R在肠道炎症和上皮损伤中的作用
- 批准号:
9927619 - 财政年份:2018
- 资助金额:
-- - 项目类别:
The function of lysophosphatidic acid receptor LPA5R in intestinal inflammation and epithelial damage
溶血磷脂酸受体LPA5R在肠道炎症和上皮损伤中的作用
- 批准号:
10406933 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Regulation of intestinal homeostasis and epithelial barrier by LPA
LPA 对肠道稳态和上皮屏障的调节
- 批准号:
9337341 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Regulation of intestinal homeostasis and epithelial barrier by LPA
LPA 对肠道稳态和上皮屏障的调节
- 批准号:
8820221 - 财政年份:2015
- 资助金额:
-- - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
-- - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
-- - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
- 批准号:
RGPIN-2018-04753 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discovery Grants Program - Individual