Molecular Regulation of Intestinal Calcium Absorption

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BACKGROUND: Calcium (Ca2+) is central to a myriad of physiological processes. Consequently it is maintained within narrow limits in plasma. This occurs via dynamic interplay between intestinal absorption, deposition/resorption from bone and by renal filtration and subsequent reabsorption. The first step is intestinal Ca2+ absorption, the focus of this NSERC funded research program, which occurs via one of two routes. Ca2+ can be absorbed by an active transcellular (through the cell) pathway, or by a passive paracellular (between epithelial cells) pathway. When there is sufficient Ca2+ in the diet, passive paracellular absorption predominates. However, 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 proposed to be the primary site of active transcellular Ca2+ absorption, although emerging evidence, including from my  program, suggests a significant 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+ and we have demonstrated a similar direct Ca2+ sensing mechanism in the intestine, but the role of this pathway in overall Ca2+ homeostasis is not clear. MODEL SYSTEMS: My research program in this area focuses on basic molecular mechanisms regulating intestinal Ca2+ absorption in mouse 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 direct measurement of Ca2+ flux across intestinal epithelium in Ussing chambers where voltage and concentration gradients can be tightly controlled, enabling the interrogation of paracellular and transcellular pathways independently. OBJECTIVES & APPROACH: The main objectives of my research program in intestinal Ca2+ absorption over the next 5 years are three-fold. 1) To delineate the regulatory role of the proximal large bowel in Ca2+ absorption. We hypothesize this is an important site of Ca2+ salvaging minimizing Ca2+ loss or when plasma Ca2+ is high, contributing significant paracellular secretion. To this end, we will measure Ca2+ absorption across proximal large bowel preparations and examine urine, fecal and plasma Ca2+ levels in wild-type and genetically modified animals. 2) We will explore the direct effect of serum Ca2+ levels on paracellular intestinal Ca2+ absorption and the role of the CaSR in this process. To do so we will use pharmacological modulators of the CaSR and knockout the CaSR in the intestine. 3) Using similar approaches we will delineate molecules in the tight junction contributing to a positive Ca2+ balance and properly mineralized bone early in life. IMPACT: These studies will delineate fundamental mechanisms maintaining mammalian Ca2+ homeostasis.