Low voluntary calcium intakes have been implicated in several diseases that afflict the U.S. population including osteoporosis, hypertension, obesity, and premenstrual syndrome. But despite many recommendations to increase calcium intake there has been almost no research to understand why calcium intakes are so low. This project will address this question by identifying and characterizing some of the physiological and genetic controls that underlie calcium consumption.
Two aims are proposed in this renewal application. The first is to identify genes responsible for the consumption of calcium.
In Aim 1. 1, congenic and consomic mice will be bred in order to isolate small chromosomal fragments containing consumption-related genes.
In Aim 1. 2, candidate genes in each fragment will be assessed using a combination of in silico methods and gene expression studies.
The second aim i s to characterize the modes and sites of action of two genes that this project has already implicated in the control of calcium consumption;the calcium-sensing receptor, Casr, and the sweet taste receptor, Tas1r3. This will be done by comparing the receptor activity of a mouse strain that avoids calcium (the C57BL/6J or B6 strain) with a strain that drinks calcium avidly (the PWK/PhJ or PWK strain). The plan is to use an HEK cell expression system to compare the physiological responses of B6 and PWK forms of CaSR and T1R3 (Aim 2.1), in situ hybridization, real-time PCR, and immunochemistry to characterize the expression of the B6 and PWK forms of CaSR and T1R3 in taste tissue (Aim 2.2), and gustatory electrophysiology to determine the functional significance of any differences between the two strains in physiological response or location of CaSR and T1R3 (Aim 2.3).
Aim 1 will lead to the discovery of genes involved in regulating the ingestion and metabolism of calcium.
Aim 2 will test the possibility that a specific receptor or pair of receptors transduce calcium taste. Understanding the mechanisms underlying calcium perception is an important step toward answering the question of why calcium intakes are so low. Given the many similarities between the mouse and human genome, such studies in mice will have direct relevance for the control of calcium consumption by humans, and thus the many diseases associated with excess or insufficient calcium intake.

Public Health Relevance

This project investigates the physiological and genetic controls of calcium intake and preference. Low calcium intakes are associated with several diseases including osteoporosis, hypertension and premenstrual syndrome. An understanding of how calcium consumption is controlled will lead to the development of effective strategies and treatments to increase calcium intake and thus reduce the incidence of these calcium- related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046791-18
Application #
8517096
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Karp, Robert W
Project Start
1994-05-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
18
Fiscal Year
2013
Total Cost
$507,503
Indirect Cost
$157,142
Name
Monell Chemical Senses Center
Department
Type
DUNS #
088812565
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Poole, Rachel L; Aleman, Tiffany R; Ellis, Hillary T et al. (2016) Maltodextrin Acceptance and Preference in Eight Mouse Strains. Chem Senses 41:45-52
Subramaniam, Selvakumar; Ozdener, Mehmet Hakan; Abdoul-Azize, Souleymane et al. (2016) ERK1/2 activation in human taste bud cells regulates fatty acid signaling and gustatory perception of fat in mice and humans. FASEB J 30:3489-3500
Tordoff, Michael G; Aleman, Tiffany R; Ellis, Hillary T et al. (2015) Normal Taste Acceptance and Preference of PANX1 Knockout Mice. Chem Senses 40:453-9
Tordoff, Michael G; Downing, Arnelle; Voznesenskaya, Anna (2014) Macronutrient selection by seven inbred mouse strains and three taste-related knockout strains. Physiol Behav 135:49-54
Voznesenskaya, Anna; Tordoff, Michael G (2013) Influence of estrous and circadian cycles on calcium intake of the rat. Physiol Behav 112-113:56-60
Ellis, Hillary T; Tordoff, Michael G; Parker, M Rockwell (2013) Itpr3 Is responsible for the mouse tufted (tf) locus. J Hered 104:295-7
Voznesenskaya, Anna; Tordoff, Michael G (2013) Influence of cross-fostering on preference for calcium chloride in C57BL/6J and PWK/PhJ mice. Physiol Behav 122:159-62
Tordoff, Michael G; Ellis, Hillary T (2013) Taste dysfunction in BTBR mice due to a mutation of Itpr3, the inositol triphosphate receptor 3 gene. Physiol Genomics 45:834-55
Tordoff, Michael G; Alarcón, Laura K; Valmeki, Sitaram et al. (2012) T1R3: a human calcium taste receptor. Sci Rep 2:496
Tordoff, Michael G; Jaji, Samira A; Marks, Jacob M et al. (2012) Macronutrient choice of BTBR.NZW mice congenic for a 21-gene region of chromosome 17. Physiol Behav 106:556-61

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