Discovery of Alpha-MSH Analogs for Skin Cancer Prevention

发现用于预防皮肤癌的 Alpha-MSH 类似物

• 批准号: 7495746
• 负责人: ZALFA ABDEL-MALEK
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495746
• 关键词: Agonist; Albinism; Alleles; Antioxidants; Apoptosis; Binding; Biological Testing; CDKN2A gene; Cadaver; Cancer-Predisposing Gene; Cell Nucleus; Cells; Corticotropin; DNA Damage; DNA Repair; DNA Sequencing Facility; Endothelin-1; Epidermis; Evaluation; Excision; Exhibits; Exposure to; Genes; Genome Stability; Goals; Hair; Hormones; Human; Incidence; Individual; Ligands; Maintenance; Malignant - descriptor; Malignant Neoplasms; MeSH Thesaurus; Mediating; Melanins; Melanocortin 1 Receptor; Melanocyte stimulating hormone; Melanogenesis; Melanosomes; Modification; Monitor; Mutation; Operative Surgical Procedures; POMC gene; Pathway interactions; Penetration; Permeability; Phenotype; Physiological; Pigmentation physiologic function; Population; Predisposition; Prevention strategy; Pro-Opiomelanocortin; Property; Proteins; Radiation Induced DNA Damage; Receptor Gene; Repression; Research Personnel; Risk; Role; Sampling; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Skin Substitutes; Skin tanning; Squamous cell carcinoma; Sun Exposure; Sunburn; Susceptibility Gene; Testing; Transmembrane Domain; UV Radiation Exposure; UV carcinogenesis; Ultraviolet Rays; Variant; Vitiligo; agouti protein; alpha-Melanocyte stimulating hormone; analog; base; cancer prevention; cancer risk; cell type; cytokine; design; eumelanin; human DNA damage; irradiation; keratinocyte; loss of function; loss of function mutation; melanocyte; melanoma; mutation carrier; novel; paracrine; peptide analog; photoprotection; programs; receptor coupling; skin cancer prevention

Skin cancer, in the form of melanoma, basal or squamous cell carcinoma, is the most commonformof cancer in the U.S.A. and is mainly caused by sun exposure, which results in DNA damage and photocarcinogenesis. There is mounting evidence for the significance of the melanocortin 1 receptor (MC1R) that is expressed on human melanocytes (hMC) and its endogenous ligands a-melanocyte stimulating hormone (a-melanocortin; a-MSH) and adrenocorticotropic hormone (ACTH) in photoprotection against skin cancer. First, activation of the MC1R by its ligands increases the synthesis of the photoprotective eumelanin, the black-brown form of melanin. Second, loss-of-function mutations in the human MC1R gene are associated with red hair phenotype, poor tanning ability and increased risk for skin cancer. Certain mutations in the gene for proopiomelanocortin, the precursorfor melanocortins, also result in red hair phenotype. Third, we discovered a novel role for a-MSH as a survival factor that rescueshMC from ultraviolet radiation (UVR>induced apoptosis and reduces DNAdamage. These effects are absent in hMC expressing loss-of-function MC1R alleles, which exhibit a reduced DNA repair capacity. Based on this evidence, the main goal of this proposal is to develop a new skin cancer preventative strategy based on utilizing potent synthetic agonists of a-MSH that can be delivered topically. Our hypothesis states that synthetic a-MSH agonists augment photoprotection in human skin and prevent skin cancer by recapitulating the stimulatory effects of a-MSH on melanogenesis, as well as on the survival and reduction in DNA damage of hMC. To investigate this hypothesis, three specific aims are proposed. The goal of Specific Aims 1and 2 is to design and synthesize potent, stable, long acting fragment analogs of a- MSH and test their ability to recapitulate all the effects of a-MSH on hMC by selectively binding and activating the MC1 R. In Specific Aim 3, the goal is to test the effects of the most effective agonists on cultured skin substitutes containing normal hMC, as well as hMCfrom individuals with a high risk for skin cancer (carriers of mutations in the MC1R or p16INK4Agene), and evaluate the possible toxicological effects and percutaneous permeability of these agonists. The significance of our proposed skin cancer prevention strategy lies in utilizing potent synthetic fragmentanalogs of a-MSH that are selective super agonists for the human MC1R and augment the photoprotection of the skin by reducing UVR-induced DNA damage and increasing eumelanin synthesis. This strategy will ultimately reduce the incidence of skin cancer particularly in high-risk population, such as individuals heterozygous for a loss-of-function MC1R allele or expressing mutations in other skin cancer susceptibility genes, such as the melanoma susceptibility gene p16INK4A.

皮肤癌，以黑色素瘤、基底细胞癌或鳞状细胞癌的形式，是最常见的形式。 在美国，癌症主要是由阳光照射引起的，阳光照射会导致DNA损伤， 光致癌作用有越来越多的证据表明黑皮质素1受体在 在人黑素细胞（hMC）上表达的MC 1 R及其内源性配体α-黑素细胞 促黑素皮质素和促肾上腺皮质激素在光防护中作用 对抗皮肤癌首先，MC 1 R通过其配体的活化增加了MC 1 R的合成。 光保护性真黑素，黑色素的黑褐色形式。第二，基因组中的功能缺失突变， 人类MC 1 R基因与红发表型、晒黑能力差和皮肤风险增加有关 癌阿黑皮素原（黑皮质素的前体）基因的某些突变也会导致 在红发表型中。第三，我们发现a-MSH作为一种存活因子， 紫外线辐射（UVR）可诱导细胞凋亡并减少DNA损伤。这些影响在 hMC表达功能丧失的MC 1 R等位基因，其DNA修复能力降低。基于此 证据，这项建议的主要目标是开发一种新的皮肤癌预防策略， 利用可局部递送的α-MSH的有效合成激动剂。我们的假设是， 合成的α-MSH激动剂通过以下方式增强人皮肤的光保护并预防皮肤癌： 概括了α-MSH对黑素生成的刺激作用，以及对存活和 减少hMC的DNA损伤。为了研究这一假设，提出了三个具体目标。的 具体目标1和2的目标是设计和合成有效的，稳定的，长效的a- MSH，并测试它们通过选择性结合和/或结合α-MSH对hMC的所有作用来概括α-MSH对hMC的所有作用的能力。 激活MC 1 R。在具体目标3中，目标是测试最有效的激动剂对 含有正常hMC的培养皮肤替代品，以及来自皮肤高风险个体的hMC， 癌症（MC 1 R或p16 INK 4A基因突变携带者），并评估可能的毒理学效应 以及这些激动剂的经皮渗透性。我们提出的皮肤癌预防的意义 策略在于利用α-MSH的有效合成片段类似物，它们是α-MSH的选择性超级激动剂， 人MC 1 R，并通过减少UVR诱导的DNA损伤来增强皮肤的光保护， 增加真黑素的合成。这一战略将最终降低皮肤癌的发病率， 在高风险人群中，例如功能丧失MC 1 R等位基因杂合或表达 其他皮肤癌易感基因的突变，如黑素瘤易感基因p16 INK 4A。