Chronic inflammation of the bowel induces a wound-healing response characterized by proliferation of mesenchymal cells and increased extracellular matrix (ECM) deposition. This fibrogenic response causes complications of stricture and obstruction. There is elevated expression of insulin-like growth factors (IGF-I and IGF-II) in animal models of chronic bowel inflammation and in the involved bowel of patients with Crohn's disease (CD). IGFs stimulate mesenchymal cell growth and potentiate proliferative actions of other hormones. We hypothesize that IGFs work together with cytokines and ECM to promote fibrosis associated with CD by stimulating enteric fibroblasts to change phenotype, increase proliferation and collagen deposition. To test this hypothesis, we propose to use an enteric fibroblast cell line isolated from the human colon (CCD-18Co) and normal, cultured human intestinal fibroblasts as model systems. First, we will assess the effects of IGF-I alone and in combination with other growth factors and cytokines implicated in CD on DNA synthesis and cell number, phenotype, as judged by alpha-smooth muscle actin, and collagen deposition, judged by collagen and collagenase gene expression and collagen production. Next, we will examine intracellular mechanisms underlying synergistic effects of IGF-I, bFGF and IL-1 on cell proliferation. This will include an examination of type I IGF receptor and IGFBPs that may modulate IGF responsiveness. In addition, a transfection approach will be used to assess the role of the AP-1 signaling in mediating IGF, bFGF, IL-1 action and their interactions. Finally, we will compare the effects of ECM extracted from healthy segment of bowel with the effects of ECM extracted from stricture of GD on DNA synthesis, cell number, differentiation, IGF expression and responsiveness to IGF.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002402-05
Application #
6175948
Study Section
Special Emphasis Panel (SRC)
Program Officer
Podskalny, Judith M
Project Start
1996-08-20
Project End
2001-08-24
Budget Start
2000-07-01
Budget End
2001-08-24
Support Year
5
Fiscal Year
2000
Total Cost
$120,426
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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