UV-induced collagen reduction: treating skin scleroderma

描述（由申请人提供）：硬皮病是一种进行性，潜在的

DESCRIPTION (provided by applicant): Scleroderma is a progressive, potentially life-threatening disease of the connective tissue that can cause hardening of the skin, and damage to lungs, heart, kidney, and gastrointestinal tract, The disease may also affect blood vessels, muscles and joints. Scleroderma typically strikes between ages 25 and 55, and women are four times more likely than men to be stricken. An estimated 300,000 persons in the United States have scleroderma. The exact causes of scleroderma are unknown, however, the hallmark of the disease process is over-production of collagen. Currently, there is no safe and effective therapy for the disease. Acute exposure to relatively low and safe doses of ultraviolet (UV) irradiation has been shown to reduce skin collagen. This reduction occurs through two simultaneous mechanisms; 1) induction of matrix metalloproteinases (MMP) that degrade skin collagen, and 2) inhibit of new procollagen synthesis. UV irradiation is composed of electromagnetic energy with wavelengths between 290-400nm, and the ability of UV to reduce skin collagen is wavelength-dependent. Short wavelengths-dependent between 290-320nm (referred to as UVB) and long wavelengths between 360-400mn (referred to as UVA1) are most effective. In light-colored people, acute exposure to UVB can cause sun turn, and chronic exposure over many years can cause skin cancer. However, the risks of sunburn and cancer from UVA1 are at least one thousand fold less than from UVB exposure. Therefore, UVA1 phototherapy holds great potential for treatment of cutaneous scleroderma in light-colored persons. In dark-colored people, the ability of UV A1 to reduce skin collagen is largely attenuated by skin pigment, likely making this form of phototherapy ineffective. However, for dark-colored people the risk of sunburn and skin cancer from UVB exposure is substantially less than for light-colored people. Therefore, UVB phototherapy for cutaneous scleroderma in dark-colored persons holds great promise. The broad, long-term objectives of this application are to optimize, evaluate, and investigate the molecular basis of UV phototherapy for the treatment of cutaneous scleroderma. The hypothesis that UV irradiation reduces cutaneous fibrosis of scleroderma by inducing MMPS and simultaneously inhibiting procollagen synthesis, and that efficacy of treatment is dependent on patients' skin pigmentation in combination with the UV wavelength used for treatment will be tested. This application contains five specific aims. Specific aims 1-3 focus on optimization of phototherapy conditions based on measurements of collagen reduction. Specific aim 1 will determine the UVA1 dose-, time- and skin color-dependence for induction of a) MMPs, b) tissue inhibitors of MMPs (TIMPS ), c) collagen degradation, and d) inhibition of procollagen synthesis in light-pigmented human skin in vivo. Specific aim 2 will determine the broadband (290-320 nm) and narrowband UVB (311-313nm) dose- and time-dependence for reduction of collagen (as described for specific aim 1) in dark-pigmented human skin in vivo. Specific aim 3 will determine the kinetics and magnitude of UVA1-induced tanning, and the impact of this tanning on subsequent UV dose dependence for reduction of collagen (as described for specific aim 1) in lightly-pigmented human skin in vivo. Specific aims 4-5 focus on phototherapy clinical trials for treatment of scleroderma. Specific aim 4 will determine, based on information obtained from Specific Aims 1-3, whether a) an optimized regimen of UVA1 irradiation improves cutaneous scleroderma in light-pigmented patients, and b) an optimized regimen of UVB, improves cutaneous scleroderma in dark-pigmented patients. Specific Aim 5 will determine whether clinical improvement in scleroderma with UV phototherapy correlates with MMP induction, collagen degradation, inhibition of procollagen synthesis, levels of profibrotic (TGF-b, CTGF, IL-4, IL-6) and antifibrotic (TNF-a, IFN-g) cytokines, and infiltrating immune cells.