UV-induced collagen reduction: treating skin scleroderma

描述(申请人提供)：硬皮病是一种进行性的，潜在的 一种威胁生命的结缔组织疾病，可导致血管硬化 皮肤，以及对肺、心脏、肾脏和胃肠道的损害， 疾病还可能影响血管、肌肉和关节。硬皮病 通常发病年龄在25岁到55岁之间，女性患病的可能性是男性的四倍 比男人更容易受到打击。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， 这种疾病的过程是胶原蛋白的过度产生。目前，没有 对这种疾病的安全有效的治疗。急性暴露于相对较低的 安全剂量的紫外线(UV)照射已被证明可以减少皮肤 胶原蛋白。这种减少是通过两个同时发生的机制实现的：1) 诱导基质金属蛋白酶(MMPs)降解皮肤胶原，以及2) 抑制新的前胶原合成。紫外线辐射由以下部分组成 波长在290-400 nm之间的电磁能量，以及 紫外线降低皮肤胶原蛋白的作用是波长依赖性的。短波长相关 在290-320 nm(称为UVB)和360-400mN之间的长波长之间 (称为UVA1)是最有效的。在浅色人群中，敏感度 暴露在UVB下会导致太阳转向，长期长期暴露在UVB下可能会 导致皮肤癌。然而，UVA1造成的晒伤和癌症的风险是 至少比UVB曝光少一千倍。因此，UVA1 光疗在中国皮肤硬皮病治疗中具有巨大潜力 浅色的人。在深色人群中，紫外线A1降低的能力 皮肤胶原蛋白在很大程度上被皮肤色素削弱，可能会使这种形式的 光疗无效。然而，对于深色皮肤的人来说，晒伤的风险 UVB照射引起的皮肤癌比浅色皮肤的皮肤癌要少得多 人民。因此，UVB光疗法治疗深色皮肤硬皮病 人有很大的希望。这方面的广泛、长期目标 应用是优化、评估和研究分子基础。 紫外线光疗治疗皮肤硬皮病。假设 紫外线照射通过诱导MMPs和MMPs减少硬皮病皮肤纤维化 同时抑制前胶原合成和治疗效果 取决于患者的皮肤色素沉着与紫外线的结合 用于治疗的波长将进行测试。此应用程序包含五个 明确的目标。具体目标1-3专注于优化光疗 基于胶原蛋白还原测量的条件。具体目标1将 确定UVA1剂量、时间和肤色的依赖关系 MMPs，b)MMPs的组织抑制物(TIMPs)，c)胶原降解，以及d) 体内浅色人皮肤中前胶原合成的抑制。 具体目标2将确定宽带(290-320 nm)和窄带UVB (311-313 nm)胶原还原的剂量和时间依赖关系(如上所述 针对特定目的：1)在活体内对暗色人皮肤进行研究。具体目标3将 确定UVA1诱导的制革的动力学和程度，以及 这种晒黑依赖于随后的紫外线剂量来减少胶原蛋白(AS 描述的特定目的1)在人体浅色皮肤中。特定的 目标4-5专注于光疗治疗硬皮病的临床试验。 具体目标4将根据从具体目标获得的信息来确定 1-3，是否a)UVA1照射的优化方案改善皮肤 浅色患者的硬皮病，以及b)UVB的优化方案， 改善黑色素患者的皮肤硬皮病。具体目标5将 确定紫外线光疗对硬皮病的临床改善作用 与基质金属蛋白酶诱导、胶原降解、抑制前胶原的关系 促肝纤维化(转化生长因子-β、结缔组织生长因子、白介素4、白介素6)的合成、水平及抗纤维化作用 (肿瘤坏死因子-a、干扰素-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.