Disorders of excessive (e.g., cirrhosis of liver, lung fibrosis) or impaired fibrogenic response to tissue injury are problems encountered frequently in contemporary clinical medicine, however, knowledge concerning the cause and pathogenesis of these conditions is fragmentary. Immune of nonimmune injury almost invariably precede fibrotic reactions. The macrophage plays a central role in the normal healing of wounds and likely plays a similar role in other fibrotic reactions. The macrophage produces two classes of biological response modifiers, [interleukin 1 (IL-1) and transforming growth factor Beta (TGF) Beta] that are capable of modulating a variety of fibroblast functions. Macrophages produce two species of IL-1 termed Alpha and Beta that share only 22% amino acid homology, yet both stimulate fibroblast proliferation and production of collagen, hyaluronic acid, collagenase, tissue inhibitor of metalloproteinase and prostaglandin (PGE2). Three species of TGFBeta, termed TGFBeta1, TGFBeta2 and TGFBeta1,2 have been identified. TGFBeta1 has been most widely studied and is the predominant species in platelet. TGFBeta1 is similar to IL-1Alpha and Beta in its effects on fibroblasts (i.e., stimulates growth and synthesis of glycosaminoglycans and collagen) except it does not stimulate collagenase production and is a potent fibroblast chemoattractant and stimulates fibronectin synthesis. TGFBeta is also produced by T cells and is found in platelets and most other normal and neoplastic cells. This application is concerned with defining the structure-function relationships of IL-1Alpha and Beta and TGFBeta1 with respect to their effects on fibroblast biology. The methodology to be used to accomplish these goals will involve 10 synthesizing peptides representing the deduced primary structure of IL- 1Alpha and Beta and TGFBeta1, 2) identifying peptides that exert similar effects as the parent molecules on fibroblasts, 3) characterizing the binding characteristics of the peptides and producing polyclonal and monoclonal antibodies against peptides to react with parent molecules as an alternative approach to study structure-function relationships, and 40 determining whether previously described T cell lymphokines having the same effects as TGFBeta1 on fibroblasts are indeed TGFBeta1 or TGFBeta1- related. These studies should contribute to our basic knowledge of the structural requirements (primary amino acid sequence) of IL-1alpha and Beta and TGFBeta1 necessary for these biological response modifiers to modulate fibroblast function and could provide new avenues of approach to the study and therapy o a variety of human disease characterized by excessive or defective fibrotic responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR026034-13
Application #
2078563
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1979-09-01
Project End
1994-11-30
Budget Start
1992-12-01
Budget End
1994-11-30
Support Year
13
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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