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| Metabolic Effects of Altered Calcium Intake in the Colon |
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Prolonged low calcium intake has been linked to the development of
several chronic diseases, including colon cancer, hypertension, and osteoporosis. It has
been proposed that disease occurs either when the body's adaptation to low calcium intake
is inadequate to maintain critical calcium regulatory system or when the constant, forced
adaptive response itself produces adverse consequences.
Colon Cancer
Despite attempts to improve the screening of high-risk populations, the incidence of colorectal
cancer is still very high, and therefore chemoprevention continues to be an important approach
to cancer control. One approach has utilized oral calcium supplementation in both preclinical
and clinical studies, based on associations between high calcium intake and decreased risk for
colorectal cancer. The basis for this calcium.s protective effect includes its
proliferative-inhibitory and differentiation-inducing effects on colonic epithelial cells, and
its complexing with bile acids and unabsorbed fatty acids in the colonic lumen thereby removing
their irritant and proliferative stimulating effects on colonic epithelial cells.
Normal, Precancerous and Neoplastic Gene Expression Patterns in Colonic Cells
A variety of genetic events modify gene expression and contribute to neoplastic transformation
of cells. These include activation of oncogenes and inactivation of tumor suppressor genes,
abrogation of mismatch repair systems, accumulations of mutant genes, loss of heterozygosity,
inactivation of important genes by methylation or loss of imprinting, and/or gene amplifications.
However, other intracellular processes in colonic epithelial cells interact to influence
transformation. Therefore, monitoring of gene expression may not only help us understand the
diverse events associated with carcinogenesis, but also the actions of chemopreventive agents
to inhibit aberrant cell growth.
Hypertension
A further objective of this study will be to measure metabolic outcomes of increased calcium
intake that may affect hypertension or bone metabolism. The ability of oral calcium
supplementation to lower blood pressure in human hypertension was first reported in 1924, and
subsequent epidemiologic data documents an inverse relation between dietary calcium intake and
the incidence of hypertension. However, in clinical trials where all hypertensive subjects are
considered together, very little quantitative benefit with calcium supplementation has been
observed.
It now appears that the underlying state of calcium metabolism may determine the biologic
response to calcium supplementation, calcium feeding either lowering or raising blood pressure
in different animal models and clinical subgroups of hypertension. The low renin, salt-sensitive
state characterized by higher basal levels of PTH and 1,25 dihydroxyvitamin D compared to
normotensive or other hypertensive subjects, exhibits a consistent depressor response to calcium
supplementation. Furthermore, in these subjects, the blood pressure response is quantitatively
proportional to the suppression of these calcium regulating hormones towards average normal
circulating levels.
These observations and others support the hypothesis mentioned above that at least some forms of
hypertension may be exacerbated by adaptive responses to conserve calcium in a calcium deficient
state. As such, common mechanisms may underlie the effects of differing dietary calcium intakes
on both colonic and vascular function.
Bone Turnover
Osteoporosis and its primary morbidity, fracture, are a major health problem in the aging
population. Although 50% to 75% of bone strength, achieved by age 30, is genetically determined,
approximately 10% of the skeleton may be undergoing remodeling at any given time, the resultant
bone turnover providing an internal (as opposed to external, dietary) supply of circulating
calcium to help maintain overall calcium homeostasis. To monitor this remodeling process, bone
specific markers such as bone specific alkaline phosphatase, osteocalcin, osteopontin, and
collagen breakdown fragments; as well as other factors such as calcium intake and 1,25 (OH)2-D3
levels, circulating estrogens and androgens, the fractional absorption of dietary calcium, and
renal calcium reabsorption have all been measured.
Therefore, to study the relation of calcium intake to genetic factors in determining calcium
and bone metabolism in the proposed protocol, we plan to follow selected parameters of bone and
mineral metabolism in subjects on oral calcium supplementation compared with basal calcium
intake values characteristic of an average American diet. In conjunction with the micro array
studies examining gene expression in selected tissues such as the colon, we may begin to
understand how calcium intake affects expression of genes that are important for bone health.
Hypothesis
We hypothesize that the chemopreventive effect of increased dietary calcium on inhibiting colonic
tumors is due to its ability to modify gene products that regulate proliferation, apoptosis, and
differentiation in colonic cells
Specific aims
To identify subsets of genes that control proliferation, apoptosis, and differentiation in human
rectal mucosal cells, whose expression is affected by dietary calcium.
Primary outcomes
Expression of genes related to cell proliferation, apoptosis and differentiation that are involved
in growth and maturation of human rectal mucosal cells.
Secondary outcomes
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Expression of additional genes involved in the cell properties noted above
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Ionic and hormonal indices of calcium metabolism
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Blood pressure and arterial stiffness
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Presence of bone disease
Researchers:
Peter Holt, holtp@mail.rockefeller.edu
Celeste Nelson, cnelson@mail.rockefeller.edu
Petr Protiva, protivp@mail.rockefeller.edu
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