OSTEOPOROSIS/DIHYDROXYVITAMIN REGULATED GENE EXPRESSION

Project Details

Description

We propose to examine changes with aging in both male and female rats in
the expression of two genes involved in intestinal calcium absorption and
in vitamin D regulated renal handling of calcium; calbindin (the vitamin D-
dependent calcium binding protein) and the vitamin D receptor (VDR). Our
hypothesis is that aging results in an alteration in the vitamin D
endocrine system and in 1,25 dihydroxyvitamin D (1,25(OH)3D3) regulated
gene expression which results in a deterioration in the normal adaptive
response to inadequate calcium intake or to calcium need. Effective
calcium deficiency as a result of defective l,25(OH)2D3 regulated gene
expression becomes a potentially more and more important problem with
advancing age, resulting in age related bone loss aggravated by calcium
deficiency. The first specific aim is to determine the effect of age and
sex on intestinal vitamin D3 receptor and calbindin gene expression and to
determine how this relates to bone mineralization. Protein and mRNA levels
(by Northern and slot blot analysis) for receptor calbindin will be
measured in 3, 6, 12 and 24 month old male and female rats. Serum calcium
and bone mineralization will also be evaluated. The second specific aim is
to determine the effect of age and sex on intestinal and renal
responsiveness to l,25(OH)2D3 or vitamin D3 and on adaptation to changes in
dietary calcium. Three, 6, 12 and 24 month old male and female rats will
be fed a strontium diet (0.8%) for 6 days to induce a functional
l,25(OH)2D3 deficiency. Animals will be sacrificed at various times after
a single intraperitoneal dose of l,25(OH)2D3. Intestinal calbindin and
1,25(OH)2D3 receptor protein and mRNA will be analyzed. In order to
determine the effect of age and sex on adaptation to dietary calcium, male
and female rats at 3, 6, 12 and 24 months will also be fed low and high
calcium diets for 10-30 days. Changes in intestinal and renal calbindin
protein and mRNA and in bone mineralization will be evaluated. No
manuscripts have been published concerning changes in female rats in
intestinal calbindin and 1,25(OH)2D3 receptor gene expression during aging.
It is indeed probable that there is some degree of age related resistance
of the intestinal mucosa and kidney to the action of 1,25(OH)2D3 during the
aging process. It is now timely to determine changes in vitamin D
regulation with aging. A greater understanding of vitamin D-dependent
adaptation in older female as well as male animals will enable us to obtain
information on how various stages of maturation and aging can affect bone
density and vitamin D-dependent gene expression. These studies could lead
to future investigations concerning genetic manipulation of calcium
responsiveness during aging.
StatusFinished
Effective start/end date9/30/918/31/96

ASJC

  • Genetics
  • Molecular Biology
  • Rheumatology

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