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 一种危及生命的结缔组织疾病，可导致 皮肤，肺，心脏，肾脏和胃肠道的损害， 疾病也可能影响血管、肌肉和关节。硬皮病 通常在25岁至55岁之间发生，女性的可能性是男性的四倍。 而不是被鞭打据估计，美国有30万人 硬皮病硬皮病的确切原因尚不清楚，然而， 疾病过程的主要特征是胶原蛋白的过度产生。目前尚无 安全有效的治疗方法。急性接触相对较低的 安全剂量的紫外线（UV）照射已被证明可以减少皮肤 胶原这种减少通过两种同时发生的机制发生; 1） 诱导降解皮肤胶原的基质金属蛋白酶（MMP），和2） 抑制新原胶原合成。紫外线照射由以下组成： 波长在290 - 400nm之间的电磁能量，以及 紫外线减少皮肤胶原蛋白是波长依赖性的。短波长相关 290 - 320nm之间（称为UVB）和360 - 400nm之间的长波长 （称为UVA 1）最有效。在浅色人种中， 暴露在UVB下会导致太阳转向，多年的长期暴露会 会导致皮肤癌。然而，UVA 1引起的晒伤和癌症的风险是在 比暴露在UVB下低至少一千倍。因此，UVA 1 光疗在治疗皮肤硬皮病方面具有很大的潜力， 浅色的人。在深色皮肤的人中，紫外线A1减少 皮肤胶原蛋白在很大程度上被皮肤色素削弱，可能使这种形式的 光疗无效。然而，对于深色皮肤的人来说， 皮肤癌的发生率远低于浅色皮肤癌。 人因此，UVB光疗皮肤硬皮病在深色 人有很大的希望。这一广泛的长期目标 应用是优化，评估和调查的分子基础， 紫外线光疗治疗皮肤硬皮病。的假设 紫外线照射通过诱导MMPS减少硬皮病皮肤纤维化， 同时抑制前胶原合成，以及治疗功效 取决于患者的皮肤色素沉着以及紫外线 将测试用于治疗的波长。该应用程序包含五个 具体目标。具体目标1 - 3侧重于光疗的优化 条件基于胶原蛋白减少的测量。具体目标1将 确定UVA 1剂量依赖性、时间依赖性和皮肤颜色依赖性，用于诱导a） MMPs，B）MMPs的组织抑制剂（TIMPS），c）胶原降解，和d） 在浅色人皮肤中抑制原胶原合成。 具体目标2将确定宽带（290 - 320 nm）和窄带UVB （311 - 313nm）的剂量和时间依赖性，以减少胶原蛋白（如所述 具体目的：1）在体内深色人皮肤中。具体目标3将 确定UVA 1诱导的晒黑的动力学和大小，以及 这种鞣制依赖于随后的UV剂量，以减少胶原蛋白（如 具体目的1）在浅色人皮肤中的体内。具体 目标4 - 5集中于用于治疗硬皮病的光疗临床试验。 具体目标4将根据从具体目标获得的信息确定 1 - 3，a）UVA 1照射的优化方案是否改善了皮肤 浅色患者的硬皮病，和B）UVB的优化方案， 改善深色皮肤患者的皮肤硬皮病。具体目标5将 确定是否临床改善硬皮病与紫外线光疗 与MMP诱导、胶原降解、前胶原抑制相关 合成、促纤维化（TGF-β、CTGF、IL-4、IL-6）和抗纤维化水平 （TNF-a，IFN-g）细胞因子和浸润性免疫细胞。

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.