Molecular regulation of intestinal calcium absorption

钙（Ca 2+）是无数生理过程的核心。因此，其在血浆中保持在较窄的范围内。这是通过肠吸收、骨沉积/再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Ca 2+吸收，通过两种途径之一发生。Ca 2+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Ca 2+时，被动的细胞旁吸收占主导地位。当膳食中钙离子浓度低时，跨细胞转运是重要的。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钙离子吸收的主要部位，尽管新出现的证据，包括我的研究计划，表明近端大肠的作用。肠道钙吸收的主要调节剂是维生素D，它增加了主动的经肠钙转运。肾脏通过钙敏感受体（CaSR）直接对细胞外Ca 2+作出反应。肠也表达CaSR，然而，其在调节Ca 2+吸收中的作用尚不清楚。我在这一领域的研究计划主要集中在调节肠道Ca 2+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Ca 2+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表达和敲低;和iii）允许在电压和浓度梯度受到严格控制的Ussing室中直接测量穿过肠上皮的Ca 2+通量，能够独立地询问细胞旁和跨细胞途径。我的研究计划在肠道钙吸收在未来5年的主要目标是三倍。1)确定近端大肠在Ca 2+吸收中的重要性。我们假设盲肠是一个Ca 2+抢救的网站，最大限度地减少Ca 2+的损失。为此，我们将测量小鼠近端大肠制备物中的Ca 2+吸收：

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