This proposal is a continuing study of cutaneous disease, manifest in part by abnormalities in cell proliferation. The goals are to obtain knowledge on the pathophysiology of psoriasis, ichthyosiform dermatoses, and other hyperproliferative skin diseases, that can be used to develop pharmacologic approaches for their clinical improvement or cure. Controls of epidermal proliferation and the influence of extracutaneous factors on these controls will be studied in normal, uninvolved, and psoriatic epidermis for clues to the etiopathogenesis of psoriasis. The biological and biochemical factors known to influence epidermal cell proliferation and differentiation, e.g., psoriatic stimulants, physiologic growth factors, and tumor promoters, will be examined in several experimental models that utilize the genetically predisposed uninvolved skin of psoriasis. A new keratinocyte model employing somatic cell fusion techniques will be used to study hyperproliferative epidermal diseases with genetic components. Fusions betwen HeLa and keratinocytes to produce immortal cell lines containing the genetic makeup of psoriasis or other genetic epidermal diseases will provide a valuable new tool for basic and therapeutic studies. By innoculating the keratinocyte hybrids into nude mice, functional expression of proliferation and differentiation abnormalities in vivo can be studied. The second new model, cyclosporine-immunesuppressed rats, which permit the long-term growth of human skin, will greatly facilitate pathophysiologic investigations of normal and diseased skin in vivo. The basic cellular mechanisms by which the folic acid antagonists and inhibitors of polyamine biosynthesis selectively influence epidermal hyperproliferation in the psoriatic process will be studied to develop pharmacological approaches for safer and more effective forms of therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR027110-10
Application #
3155510
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1979-09-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Weinstein, G D; White, G M (1993) An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 28:454-9
Morganroth, G S; Chan, L S; Weinstein, G D et al. (1991) Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells. J Invest Dermatol 96:333-40
Weinstein, G D; Jeffes, E; McCullough, J L (1990) Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol 95:49S-52S
Weinstein, G D; Jeffes, E; McCullough, J L (1990) Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol 95:49S-52S