GROWTH FACTOR/CYTOKINE INTERACTIONS IN MESENCHYMAL CELLS

间充质细胞中生长因子/细胞因子的相互作用

• 批准号: 2443764
• 负责人: JOLANTA B PUCILOWSKA
• 金额: $ 8.77万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-20 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443764
• 关键词: Crohn's disease; autoradiography; binding proteins; cell differentiation; clinical research; colon; extracellular matrix; fibroblast growth factor; fibroblasts; growth factor receptors; human subject; insulinlike growth factor; interleukin 1; intermolecular interaction; mesenchyme; nucleic acid biosynthesis; oligonucleotides; polymerase chain reaction; transcription factor; transfection

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.

肠道的慢性炎症会引起伤口愈合反应