The long term goals of this proposal are to define the roles of GH, IGF-I and IGFBPs in intestinal adaptation. It is established that GH and IGF-I stimulate increases in bowel mass but the cellular mechanisms by which they act are not defined. IGF-I may regulate bowel growth by endocrine and by paracrine actions. IGF-I alone characteristically exerts relatively weak mitogenic or differentiative effects. More potent actions are observed when IGF-I interacts with other hormones or growth factors such as growth hormone (GH) and members of the Epidermal Growth Factor (EGF) family. A family of six high affinity IGF binding proteins (IGFBPS 1- 6) appear to be major determinants of IGF-I action, cellular sites of IGF-I action and interactions of IGF-I with other hormones and growth factors. We have demonstrated that three IGFBPs, IGFBP 3, 4 and 5, are expressed within distinct bowel layers and cell types in the small intestine. Expression of each of these intestinal IGFBPs also is regulated selectively in response to different stimuli of adaptive growth. These observations underlie two hypotheses under test in the present proposal: 1. IGF-I regulates proliferation, survival and/or differentiated function of multiple cell types in small intestine during adaptive growth. 2. Cell type specific actions of IGF-I in response to different stimuli are mediated by interactions with IGFBPs, GH and other intestinal growth factors.
Specific aims to test these hypotheses include:
Aim 1 : to define the cellular mechanisms by which GH and IGF-I regulate bowel mass and function in vivo in transgenic mice with GH and IGF-I excess or GH deficiency and IGF-I excess.
Aim 2 : to assess direct actions and mechanisms of IGF-I action in model intestinal epithelial and intestinal fibroblast cell lines (IEC-6 cells and CCD-18 Co cells).
Aim 3 : to test whether there are cell-specific alterations in specific IGFBPs during adaptive growth of different bowel layers in response to myenteric denervation.
Aim 4 : to define the role of IGFBP5 in growth of enteric smooth muscle by using targeted ablation of the IGFBP5 gene in transgenic mice.
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