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。

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.