Molecular regulation of intestinal calcium absorption

肠道钙吸收的分子调节

• 批准号: RGPIN-2015-05842
• 负责人: Alexander, Robert
• 金额: $ 2.04万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682594
• 关键词: Molecular; regulation; intestinal; calcium; absorption

Calcium (Ca2+) is central to a myriad of physiological processes. Consequently it is maintained within narrow limits in plasma. This is accomplished by dynamic interplay between intestinal absorption, deposition/resorption from bone and by filtration and subsequent reabsorption by the kidney. The first step is intestinal Ca2+ absorption, which occurs via one of two routes. Ca2+ is absorbed via an active transcellular (through the epithelial cell) pathway, or by a passive paracellular pathway (between epithelial cells). When adequate amounts of Ca2+ are present in the diet, passive paracellular absorption predominates. When, dietary Ca2+ is low, transcellular transport is important. This is mediated by a series of transport and carrier events (Fig 1). The duodenum is thought to be the primary site of active transcellular Ca2+ absorption, although emerging evidence, including from my research program, suggests a role for the proximal large bowel. The primary regulator of intestinal Ca2+ absorption is vitamin D, which increases active transintestinal Ca2+ transport. The kidney responds directly to extracellular Ca2+ via the calcium sensing receptor (CaSR). The intestine also expresses the CaSR, however, its role in regulating Ca2+ absorption is unknown.*** My research program in this area focuses on basic molecular mechanisms regulating intestinal Ca2+ absorption. I use murine models because they: i) permit the study of Ca2+ homeostasis within the context of the whole organism; ii) are readily amenable to pharmacologic and genetic approaches, including over-expression and knockdown of key players; and iii) permit the direct measurement of Ca2+ flux across intestinal epithelium in Ussing chambers where voltage and concentration gradients are tightly controlled,  enabling the interrogation of paracellular and transcellular pathways independently.*** The main objectives of my research program in intestinal Ca2+ absorption over the next 5 years are three-fold. 1) To determine the importance of proximal large bowel in Ca2+ absorption. We hypothesize the cecum is a site of Ca2+ salvaging minimizing Ca2+ loss. To this end, we will measure Ca2+ absorption across proximal large bowel preparations of mice: i) treate

钙(Ca~(2+))在多种生理过程中起着中心作用。因此，它在血浆中也保持在狭窄的范围内。这是通过肠道吸收、骨骼的沉积/吸收以及过滤和随后的肾脏重吸收之间的动态相互作用实现的。第一步是肠道对钙的吸收，这通常通过两种途径之一发生。Ca~(2+)通过主动的跨细胞途径(通过上皮细胞)吸收，或通过被动的细胞旁途径吸收(上皮细胞之间)。当饮食中存在足够数量的钙离子时，被动的细胞旁吸收占主导地位。当膳食中的钙离子含量较低时，跨细胞转运就很重要。这是由一系列运输和承运人事件调节的(图1)。十二指肠被认为是活跃的跨细胞钙吸收的主要部位，尽管包括我的研究项目在内的新证据表明，大肠近端也有作用。肠道钙吸收的主要调节剂是维生素D，它增加了主动的跨肠钙转运。肾脏通过钙感应受体(CaSR)直接对细胞外钙离子产生反应。肠道也表达CaSR，但它在调节钙吸收中的作用尚不清楚。*我在这方面的研究重点是调节肠道钙吸收的基本分子机制。我使用小鼠模型是因为：i)它们允许在整个有机体的背景下研究钙离子动态平衡；ii)易于采用药理学和遗传学方法，包括关键角色的过度表达和击倒；以及iii)允许在电压和浓度梯度受到严格控制的Ussing小室中直接测量跨越肠上皮的钙流量，从而能够独立地询问细胞旁和跨细胞途径。*我在未来5年的肠道钙吸收研究计划的主要目标有三个。1)确定近端大肠在钙吸收中的重要性。我们假设盲肠是一个挽救钙离子的部位，使钙离子损失最小化。为此，我们将测量小鼠近端大肠准备物对钙的吸收：i)治疗