Calcium Receptor Action in Childhood Diarrhea

儿童腹泻中钙受体的作用

基本信息

  • 批准号:
    8679694
  • 负责人:
  • 金额:
    $ 12.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-04-10 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This application outlines a career development plan for me to become an independent investigator researching novel antidiarrheal mechanisms and therapeutic approaches for diarrhea in children. I am now in my first faculty position as an Assistant Professor of Pediatric Gastroenterology in the Department of Pediatrics at the University of Florida. I have a strong background in fluid, electrolyte and nutrition physiology, having received a Ph.D. in ion transport physiology at Karolinska Institute and postdoctoral training in GI physiology under the late Dr. Steven Hebert at Yale University, where I initiated my interest in the calcium/nutrient-sensing receptor (CaSR) in the gut. I am now working with my mentor, Dr. Mansour Mohamadzadeh, studying the unique antidiarrheal function of this nutrient sensing receptor. Acute infectious diarrhea is a worldwide problem, especially among infants, young children and immune-compromised patients. Sadly, 1.3 million children die each year, not because of the infections causing diarrhea, but due to the associated dehydration. The pro-absorptive Oral Rehydration Solution (ORS) is the only recommended oral therapy for children with acute diarrhea, yet it neither reduces diarrhea/secretion nor alters the overly activ enteric nerve (ENS) activity/motility - both significant contributors to diarrhea. The overarching question of this application is the following: can we develop a novel anti-diarrheal therapy that i as simple and has both pro-absorptive and anti-secretory properties while reducing ENS activity and motility? Based upon preliminary data, I hypothesize that the intestinal CaSR is a likely candidate for developing such a therapeutic. The preliminary data show that CaSR is expressed in the gut epithelium, both in the absorbing surface epithelium and secreting crypts. Also, CaSR is densely present in the ENS, both in the fluid-modulating submucosal plexus and the motility-modulating myenteric plexus. Furthermore, using isolated microperfused crypts, it was observed that activating the epithelial CaSR reversed enterotoxin-induced fluid movement from net secretion to net absorption. To test the hypothesis, the following specific aims have been developed: Aim 1: will define the ion transport mechanisms influenced by epithelial CaSR. These studies will be performed in ex vivo intestinal segments using classical physiological techniques that involve the use of Ussing chamber, pH stat titration and measurement of isotope fluxes. Aim 2: will describe influences on gut motility by neuronal CaSR by examining CaSR modulations of evoked contractions in intestinal muscle strips in vitro and gastro-intestinal transit in vivo. Lastly, Aim 3: will assess CaSR anti-diarrheal effect in vivo by examining CaSR effects in (a) enterotoxin (cholera toxin, E coli STa & Rotavirus NSP4)- and (b) Norovirus- induced diarrhea. It is anticipated that this project will yield new insights into intestinal physiology and may lead to the development of novel CaSR-based therapeutics for acute diarrhea. Abbreviations: Ca2+i, intracellular Ca2+; Ca2+o, extracellular Ca2+; CaSR, Ca2+-sensing receptor; CTX, cholera toxin; ENS, enteric nervous system; i.v., intravenously; i.p., intraperitoneally; NSP4, rotavirus non structure protein 4 enterotoxin; ORS, oral rehydration solution; p.o., per os; SCFA, short-chain fatty acids, STa, E. coli heat stable enterotoxin;
描述(由申请人提供):本申请概述了我的职业发展计划,成为一名独立的研究人员,研究儿童腹泻的新型抗腹泻机制和治疗方法。我现在是我的第一个教师职位,在佛罗里达大学儿科系担任儿科胃肠病学助理教授。我在液体,电解质和营养生理学方面有很强的背景,获得了博士学位。我在卡罗林斯卡研究所从事离子转运生理学研究,并在耶鲁大学接受已故Steven Hebert博士的GI生理学博士后培训,在那里我开始对肠道中的钙/营养感应受体(CaSR)产生兴趣。我现在和我的导师Mansour Mohamadzadeh博士一起研究这种营养感应受体的独特抗衰老功能。 急性感染性腹泻是一个世界性的问题,特别是在婴儿,幼儿和免疫功能低下的患者中。可悲的是,每年有130万儿童死亡,不是因为感染导致腹泻,而是由于相关的脱水。促吸收口服补液溶液(ORS)是唯一推荐用于急性腹泻儿童的口服治疗,但它既不能减少腹泻/分泌,也不能改变过度活跃的肠神经(ENS)活动/运动-这两者都是腹泻的重要因素。该应用的首要问题如下:我们能否开发一种新的抗结肠炎疗法,该疗法既简单又具有促吸收和抗分泌特性,同时降低ENS活性和运动性?根据初步数据,我假设肠道CaSR是开发这种治疗方法的可能候选者。初步数据显示,CaSR在肠上皮中表达,在吸收表面上皮和分泌隐窝中均表达。此外,CaSR密集地存在于ENS中,在液体调节粘膜下神经丛和运动调节肌间神经丛中。此外,使用分离的微灌注隐窝,观察到激活上皮CaSR逆转肠毒素诱导的流体运动从净分泌到净吸收。为了验证这一假设,已经开发了以下具体目标:目标1:将定义上皮CaSR影响的离子转运机制。这些研究将使用经典生理学技术在离体肠段中进行,这些技术涉及使用Ussing室、pH统计滴定和同位素通量测量。目标二:将通过检查体外肠肌条和体内胃肠传输中诱发收缩的CaSR调制来描述神经元CaSR对肠运动的影响。最后,目标3:将通过检查CaSR在(a)肠毒素(霍乱毒素,大肠杆菌STa和轮状病毒NSP 4)和(B)诺如病毒诱导的腹泻中的作用来评估CaSR的体内抗腹泻作用。预计该项目将对肠道生理学产生新的见解,并可能导致开发基于CaSR的新型急性腹泻治疗方法。缩略语:Ca 2 +i,细胞内Ca 2 +; Ca 2 +o,细胞外Ca 2 +; CaSR,Ca 2+敏感受体; CTX,霍乱毒素; ENS,肠神经系统; i. v.,静脉内; i. p.,腹膜内; NSP 4,轮状病毒非结构蛋白4肠毒素; ORS,口服补液溶液; p.o.,SCFA,短链脂肪酸,STa,E.大肠杆菌热稳定肠毒素;

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)

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Sam X Cheng其他文献

Inability to reduce morbidity of diarrhea by ORS: can we design a better therapy?
口服补液盐不能降低腹泻发病率:我们能否设计出更好的治疗方法?
  • DOI:
    10.1038/pr.2017.295
  • 发表时间:
    2018-01-03
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Jane E Harrell;Sam X Cheng
  • 通讯作者:
    Sam X Cheng

Sam X Cheng的其他文献

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{{ truncateString('Sam X Cheng', 18)}}的其他基金

Next generation ORS: Randomized controlled trial comparing ORS with calcium vs standard ORS in reducing severity of adults with acute watery diarrhea
下一代 ORS:比较 ORS 加钙与标准 ORS 在降低成人急性水样腹泻严重程度方面的随机对照试验
  • 批准号:
    10593311
  • 财政年份:
    2023
  • 资助金额:
    $ 12.19万
  • 项目类别:
Calcium Receptor Action in Childhood Diarrhea
儿童腹泻中钙受体的作用
  • 批准号:
    9245724
  • 财政年份:
    2014
  • 资助金额:
    $ 12.19万
  • 项目类别:

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