Molecular regulation of intestinal calcium absorption

钙（Ca2+）是无数生理过程的核心。因此，它在等离子体中维持在狭窄的范围内。这是通过肠道吸收、骨沉积/再吸收、过滤和随后的肾脏再吸收之间的动态相互作用来完成的。第一步是肠道Ca2+吸收，它通过两种途径之一发生。Ca2+通过主动的跨细胞（通过上皮细胞）途径或被动的细胞旁途径（上皮细胞之间）吸收。当饮食中有足够的Ca2+时，被动的细胞旁吸收占主导地位。当饮食Ca2+低时，跨细胞运输是重要的。这是由一系列转运和载体事件介导的（图1）。十二指肠被认为是活跃的跨细胞Ca2+吸收的主要部位，尽管新出现的证据，包括我的研究项目，表明近端大肠的作用。肠道Ca2+吸收的主要调节剂是维生素D，它增加了活跃的跨肠Ca2+运输。肾脏通过钙感应受体（CaSR）直接响应细胞外Ca2+。肠道也表达CaSR，然而，其在调节Ca2+吸收中的作用尚不清楚。***我的研究方向是肠道Ca2+吸收的基本分子机制。我使用小鼠模型是因为它们：I)允许在整个生物体的背景下研究Ca2+稳态；Ii)易于采用药理学和遗传学方法，包括过度表达和敲低关键基因；iii)允许在Ussing室中直接测量穿过肠上皮的Ca2+通量，其中电压和浓度梯度受到严格控制，从而能够独立地询问细胞旁和跨细胞途径。***我在未来5年肠道Ca2+吸收研究计划的主要目标有三个方面。1)确定近端大肠在Ca2+吸收中的重要性。我们假设盲肠是Ca2+抢救的场所，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+稳态的药理学调节剂处理；ii)饲喂改变后的含Ca2+饲料；iii)缺乏跨细胞Ca2+通量所需成分的转基因小鼠。2)使用类似的方法，我们将描绘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在这一过程中的作用。为此，我们将使用CaSR的药理学调节剂，在小鼠肠道中敲低和过表达CaSR。这些研究将解决介导Ca2+稳态的基本机制

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.**