UV-induced collagen reduction: treating skin scleroderma

紫外线诱导的胶原蛋白减少：治疗皮肤硬皮病

• 批准号: 6512141
• 负责人: Sewon Kang
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-26 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512141
• 关键词: biopsy; collagen; collagenase; colorimetry; cytokine; disease /therapy duration; enzyme activity; enzyme biosynthesis; enzyme linked immunosorbent assay; human subject; human therapy evaluation; immunologic skin test; in situ hybridization; outcomes research; patient oriented research; phototherapy; pigmentation; polymerase chain reaction; procollagen; protein degradation; radiation therapy dosage; scleroderma; statistics /biometry; tissue inhibitor of metalloproteinases; ultraviolet radiation; ultraviolet therapy

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.

描述（由申请人提供）：硬皮病是一种进行性、潜在的疾病 危及生命的结缔组织疾病，可导致结缔组织硬化 皮肤，并对肺、心脏、肾脏和胃肠道造成损害， 疾病还可能影响血管、肌肉和关节。硬皮病 通常发生在 25 岁至 55 岁之间，女性的可能性是其四倍 比男人更受打击。据估计，美国有 300,000 人 硬皮病。硬皮病的确切原因尚不清楚，但其标志是 疾病过程的关键是胶原蛋白的过度产生。目前，没有 安全有效地治疗该疾病。急性暴露相对较低 安全剂量的紫外线 (UV) 照射已被证明可以减少皮肤 胶原。这种减少是通过两种同时发生的机制实现的： 1） 诱导降解皮肤胶原蛋白的基质金属蛋白酶 (MMP)，以及 2) 抑制新的前胶原合成。紫外线照射的组成为 波长在290-400nm之间的电磁能，以及 减少皮肤胶原蛋白的紫外线与波长有关。取决于短波长 290-320nm之间（简称UVB）和360-400mn之间的长波长 （简称UVA1）最为有效。在浅色人种中，急性 暴露于 UVB 会导致日晒，长期暴露于 UVB 会导致日晒斑。 导致皮肤癌。然而，UVA1 导致晒伤和癌症的风险却很高。 比 UVB 暴露至少减少一千倍。因此，UVA1 光疗在治疗皮肤硬皮病方面具有巨大潜力 浅色人种。对于深色肤色的人来说，UV A1 减少的能力 皮肤胶原蛋白在很大程度上被皮肤色素削弱，可能导致这种形式的 光疗无效。然而，对于深色肤色的人来说，晒伤的风险 UVB 暴露引起的皮肤癌远低于浅色人群 人们。因此，UVB光疗治疗深色皮肤硬皮病 人有很大的前途。该计划的广泛、长期目标 应用程序是为了优化、评估和研究分子基础 紫外线光疗用于治疗皮肤硬皮病。假设 紫外线照射通过诱导 MMPS 和减少硬皮病的皮肤纤维化 同时抑制原胶原合成，治疗效果 取决于患者的皮肤色素沉着与紫外线的结合 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 侧重于光疗优化 基于胶原蛋白减少测量的条件。具体目标1将 确定 UVA1 剂量、时间和肤色依赖性，以诱导 a) MMP，b) MMP 组织抑制剂 (TIMPS)，c) 胶原蛋白降解，以及 d) 体内浅色人类皮肤中原胶原合成的抑制。 具体目标 2 将确定宽带 (290-320 nm) 和窄带 UVB (311-313nm) 胶原蛋白减少的剂量和时间依赖性（如所述 针对特定目标 1) 体内深色人类皮肤。具体目标3将 确定 UVA1 引起的晒黑的动力学和程度，以及 这种晒黑对随后胶原蛋白减少的紫外线剂量依赖性（如 描述了特定目标 1) 在体内浅色人类皮肤中的情况。具体的 目标 4-5 重点关注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，a)优化的UVA1照射方案是否改善皮肤 浅色患者的硬皮病，以及 b) UVB 的优化方案， 改善深色色素患者的皮肤硬皮病。具体目标 5 将 确定紫外线光疗是否能改善硬皮病的临床症状 与 MMP 诱导、胶原蛋白降解、前胶原蛋白抑制相关 合成、促纤维化水平（TGF-b、CTGF、IL-4、IL-6）和抗纤维化水平 （TNF-a、IFN-g）细胞因子和浸润免疫细胞。