MOLECULAR STUDIES OF GROWTH FACTORS DURING DEVELOPMENT

Project Details

Description

DESCRIPTION (adapted from investigator's abstract): Multiple components
of the insulin-like growth factor (IGF) system have been shown by gene
targeting to be required for normal growth and differentiation in the
mouse. The major goal of this proposal is to determine the in vivo role
during development of the six-member IGF binding protein (IGFBP) family,
which is thought to be a major regulator of the IGF system at multiple
levels. It is generally thought that circulating IGFBPs primarily
function to inhibit IGF action, while tissue-associated IGFBPs can
enhance or attenuate IGF action and potentially subserve additional
roles. They have produced by gene targeting mice that lack IGFBP-2, a
prominent fetal IGFBP, and have shown that these mice exhibit a reduced
adult spleen size. In addition, the serum of adult mice homozygous for
the IGFBP-2 mutation has increased levels of several additional IGFBPs
that themselves are expressed by early post-implantation development.
To extend their functional analysis of the IGFBP system, they will
produce by gene targeting mice lacking functional copies of four
additional IGFBPs (BPs-- 3, -4, -5, and -6) that each have distinct
spatial and temporal expression patterns in the embryo that suggest
prospective developmental roles in multiple organ systems.
Developmental deficits in mutant mice will be identified; if individual
homozygous mutants are viable, postnatal growth, organ histopathology
and endocrine status will he evaluated with specific emphasis on
analysis of the connective tissue and urogenital systems, sites that
would appear to be particularly sensitive to IGFBP mutation. As mutant
lines are produced, combinatorial mating to produce strains defective in
several IGFBPs will be initiated with the expectation that additional
required roles for this gene family during development will emerge.
They also propose to continue to characterize the IGFBP-2 mutation in
combination with other IGF system mutants. They will produce mice
doubly-homozygous for the IGFBP-2 mutation and other alleles (including
a null allele for H19) that increase the circulating levels of IGF-2
either pre- or post-natally. They will determine whether these genetic
challenges in the absence of IGFBP-2 alter growth, further increase
expression of the other IGFBPs, or reverse the deficit in adult spleen
size of homozygous IGFBP-2 mice. These studies will clarify the
specific role of IGFBP-2 as well as additional IGFBPs in regulating IGF-2
activity. Taken together, the proposed experiments will determine the
role of the IGFBP system in prenatal growth and in development of
several organ systems, test the hypothesis that IGFBPs functionally
compensate for each other during development, and produce new lines of
mutant mice lacking specific IGFBPs that will be useful models for
developmental and endocrine manipulation.
StatusFinished
Effective start/end date1/1/9011/30/02

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $312,195.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke

ASJC

  • Genetics
  • Molecular Biology
  • Cell Biology
  • Embryology

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