FUNCTIONAL STUDIES OF IGF BINDING PROTEIN-1

Project Details

Description

The insulin-like growth factor binding protein-1 (IGFBP-1) is uniquely
characterized among the family of IGF binding proteins by the
characteristics that (1) circulating IGFBP-1 levels inversely correlate
with fetal birthweights in multiple paradigms in both humans and rodents
and (2) IGFBP-1 is tightly regulated by insulin and dramatically elevated
under conditions of hypoinsulinemia such as occurs in insulin-dependent
diabetes mellitus (IDDM). The exact in vivo functions of IGFBP-1 are
unknown, however, considerable evidence supports the hypothesis that the
family of six IGFBPs are major modulators of IGF-I and IGF-II, mitogenic
peptides that mediate growth and metabolism. The proposed project will
test the hypothesis that IGFBP-1 is a major regulator of IGF availability
and has a critical role in fetal and postnatal growth and in glucose
counterregulation. This hypothesis leads to the following testable
predictions that: (1) IGFBP-1 will be present in embryonic circulation
by mid-gestational ages, as early as IGFs are known to act in fetal
growth. (2) IGFBP-1 deficiency during development will result in
increased fetal and neonatal growth. (3) IGFBP-1 will attenuate growth
and metabolic effects of chronic and acute IGF-1 challenge. (4) Chemical
induction of IDDM in IGFBP-1 deficient mice will result in attenuation
of secondary complications of diabetes that are the result of decreased
IGF availability. (5) Either deficiency or overexpression of IGFBP-1 will
alter the rate and amount of kidney hypertrophy associated with both
uninephrectomy and chemically-induced IDDM. The proposed research will
directly test these predictions using, in part, a powerful approach to
establish a genetic mouse model that is deficient in IGFBP-1. These
studies will provide a better understanding of the in vivo role of IGFBP-
1 in growth and metabolism during normal states and in specific
pathological conditions.
StatusFinished
Effective start/end date1/1/9512/31/99

ASJC

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

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