IGF BINDING PROTEIN-3--REGULATION AND BIOLOGICAL ACTIONS

Project: Research project

Project Details

Description

The insulin-like growth factors (IGFs) are polypeptides structurally
related to insulin that have potent growth-promoting and insulin-like
effects in vitro and in vivo. Unlike insulin, IGFs associate with distinct
proteins present in plasma and other biological fluids that may be key
determinants of IGF bioavailability and bioactivity. At present, the
factors regulating the production of the various IGF binding proteins and
the precise role of the different proteins in modulating IGF action are
unknown. Our central hypothesis is that IGF binding proteins are integral
components of IGF physiology that define and coordinate IGF and insulin
action at the level of the target cell. In this proposal, we focus on the
predominant circulating IGF binding protein in adults: IGFBP-3. The
Specific Aims of this research project are (1) to determine the hormonal
control of IGFBP-3 synthesis and secretion under defined conditions, (2) to
ascertain the cellular mechanisms of IGFBP-3 action, (3) to assess
quantitative and qualitative changes in IGFBP-3 production and function
with aging in vitro, and (4) to define the regulation of IGFBP-3 in vivo.
Major hypotheses to be tested are directed toward deciphering the complex
relationship between IGF-I peptide and IGFBP-3: (a) IGF-I is a primary
regulator of IGFBP-3, acting via both receptor-mediated and receptor-
independent mechanisms, (b) IGFBP-3 regulates type I IGF receptor
signalling at the level of ligand binding, and (c) Factors that alter
IGFBP-3 availability can modulate IGF-I action independent of changes in
IGF-I peptide or receptor concentration.

An essential feature of this proposal is the development of appropriate
models for evaluating the regulation and biological effects of IGFBP-3. We
will employ cultured normal and SV40-transformed human fibroblasts and
normal bovine fibroblasts because of their unique and complementary
attributes well suited for investigations into IGFBP-3 cellular physiology.
Information derived from these in vitro systems will be integrated with in
vivo studies.

The principal investigator has expertise in the various techniques of
cellular physiology, molecular biology, and biochemistry necessary for the
success of this proposal. These studies will help clarify the integrated
role if IGFs and IGF binding proteins in the control of cell growth.
Knowledge of the structure, function, and regulation of IGFBP-3 will have
major implications for our understanding of the physiology and
pathophysiology of IGF-I, as well as for applications of IGF-I in clinical
medicine.
StatusFinished
Effective start/end date5/1/924/30/96

ASJC

  • Medicine(all)