DISCOVERING THE SPACIAL AND TEMPORAL COMPLEXITY OF INTESTINAL 1ALPHA,25-DIHYDROXYVITAMIN D ACTION

The primary role of 1,25(OH)₂D and the vitamin D receptor (VDR) during growth is to mediate intestinal calcium (Ca) absorption by regulating the expression of genes (e.g., Trpv6, S100g) that control Ca fluxes through enterocyte. In contrast to the well-defined role during rapid growth, the understanding of 1,25(OH)₂D signaling in post-growth, mature adult or the elderly is poor. Some observational studies suggest intestinal 1,25(OH)₂D signaling is not important to Ca absorption and bone for mature adult. In the elderly, intestine develops resistance to 1,25(OH)₂D action which might be due to age-related reductions in intestinal VDR level. In addition, there is lack of evidence that directly tests the role of 1,25(OH)₂D action in the distal intestine post-growth. My dissertation research focuses on discovering the importance of 1,25(OH)₂D signaling from both the temporal and spatial perspectives. By using 4-month old, whole intestine or large intestine VDR knockout mice, we found that for mature mice, 1,25(OH)₂D signaling plays a minimal role in regulating Ca absorption and protecting bone mass when dietary Ca intake is adequate. In contrast, 1,25(OH)₂D signaling in the whole intestine, and to a lesser extent the proximal colon, is critical to upregulate Ca absorption and protect bone when dietary Ca intake is low. Next, we proved that the Ca absorptive machinery in the proximal colon can be locally stimulated to enhance the expression of Trpv6 by 1,25(OH)₂D released from glycoside and glucuronide forms of calcitriol. Furthermore, our transcriptomic analysis on 1,25(OH)₂D-regulated genes in the duodenum of mature (4-month old), middle-aged (11.5-month old), and old (20.5-month old) mice suggest although aging did reduce the induction of some genes by 1,25(OH)₂D, this effect is not universally present across the genome and it is not related to intestinal Vdr expression. The findings from my dissertation research serve as a foundation for future research to identify a) the potential of specifically targeting proximal colon to increase intestinal Ca absorption and protect bone in adult; b) the molecular mechanisms that contribute to the aging-associated, non-universal resistance to 1,25(OH)₂D action.