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, RTodd
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=643726
• 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) treated with calciotropic hormones or pharmacological regulators of Ca2+ homeostasis; ii) fed altered Ca2+-containing diets; and iii) genetically modified mice lacking components required for transcellular Ca2+ flux. 2) Using similar approaches we will delineate the molecules responsible for maintaining a positive Ca2+ balance early in life. 3) We will explore the direct effect of serum Ca2+ levels on intestinal Ca2+ absorption and the role of the CaSR in this process. To do so we will use pharmacological modulators of the CaSR and both knockdown and over-express the CaSR in the intestine of mice. These studies will address fundamental mechanisms mediating Ca2+ homeostasis.**

钙 (Ca2+) 对于许多生理过程至关重要。因此，它在血浆中保持在狭窄的范围内。这是通过肠道吸收、骨骼沉积/再吸收之间的动态相互作用以及通过肾脏的过滤和随后的重吸收来实现的。第一步是肠道 Ca2+ 吸收，通过两条途径之一进行。 Ca2+ 通过主动跨细胞（通过上皮细胞）途径或被动细胞旁途径（上皮细胞之间）吸收。当饮食中存在足够量的 Ca2+ 时，被动细胞旁吸收占主导地位。当饮食中 Ca2+ 较低时，跨细胞转运就很重要。这是由一系列运输和载体事件介导的（图 1）。十二指肠被认为是主动跨细胞 Ca2+ 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近端大肠也发挥着作用。肠道 Ca2+ 吸收的主要调节剂是维生素 D，它可以增加活性的跨肠 Ca2+ 转运。肾脏通过钙传感受体 (CaSR) 直接对细胞外 Ca2+ 做出反应。肠道也表达 CaSR，但其在调节 Ca2+ 吸收中的作用尚不清楚。*** 我在该领域的研究项目侧重于调节肠道 Ca2+ 吸收的基本分子机制。我使用小鼠模型，因为它们：i) 允许在整个生物体的背景下研究 Ca2+ 稳态； ii) 易于接受药理学和遗传学方法，包括关键参与者的过度表达和敲除； iii) 允许在严格控制电压和浓度梯度的 Ussing 室中直接测量穿过肠上皮的 Ca2+ 通量，从而能够独立询问细胞旁和跨细胞途径。*** 我的未来 5 年肠道 Ca2+ 吸收研究计划的主要目标有三个。 1) 确定近端大肠在Ca2+吸收中的重要性。我们假设盲肠是 Ca2+ 回收的场所，可最大限度地减少 Ca2+ 损失。为此，我们将测量小鼠近端大肠制剂的 Ca2+ 吸收：i) 用促钙激素或 Ca2+ 稳态药物调节剂治疗； ii) 饲喂经过改变的含 Ca2+ 饮食； iii) 缺乏跨细胞 Ca2+ 流动所需成分的转基因小鼠。 2) 使用类似的方法，我们将描述负责在生命早期维持正 Ca2+ 平衡的分子。 3) 我们将探讨血清Ca2+水平对肠道Ca2+吸收的直接影响以及CaSR在此过程中的作用。为此，我们将使用 CaSR 的药理学调节剂，并在小鼠肠道中敲低和过度表达 CaSR。 这些研究将解决介导 Ca2+ 稳态的基本机制。**