Targeting the Melanocortin 1 Receptor by Selective Small Analogs of α-Melanocortin for Melanoma Prevention
通过选择性α-黑皮质素小类似物靶向黑皮质素 1 受体预防黑色素瘤
基本信息
- 批准号:9898307
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AfghanistanAgeAge-YearsAgonistAmino AcidsAnimal ModelAntiinflammatory EffectAntioxidantsApoptosisAutopsyBRAF geneBiological AssayBiological AvailabilityBlood TestsBlood specimenCDKN2A geneCaucasiansCellsChemopreventionChemopreventive AgentClimateConduct Clinical TrialsCosmeticsCountryCoupledCutaneousCutaneous MelanomaDNA DamageDNA RepairDNA photoproductsDataDevelopmentDiffusionDiseaseDrug KineticsEpidermisEtiologyExperimental ModelsExposure toFamily suidaeFormulationGeneral PopulationGenome StabilityGenotypeGeographic LocationsGoalsHairHormonesHumanImmunodeficient MouseImmunosuppressionIn VitroIncidenceIndividualInvestigational New Drug ApplicationIraqLegal patentLightMeasurementMelanocortin 1 ReceptorMembraneMethodsMilitary PersonnelModelingMorbidity - disease rateMutationNot Hispanic or LatinoNude MiceOutcomePeptidesPhenotypePhysiologicalPigmentation physiologic functionPigmentsPopulationPreventionPrevention strategyPropertyProteinsPublishingReceptor GeneReceptor SignalingReportingRiskSeminalSkinSkin CancerSkin PigmentationSkin SubstitutesSkin tanningSoldierSun ExposureSusceptibility GeneSystemTestingThe SunTherapeuticTissue SampleTopical agentTopical applicationToxicologyUV Radiation ExposureUV inducedUV induced DNA damageUltraviolet RaysVariantVeteransage groupalpha-Melanocyte stimulating hormoneanalogbasecancer diagnosiscancer riskeumelaningenetic varianthigh riskhigh risk populationhormone analoghot climatein vivo Modelkeratinocytelipophilicityloss of functionlysylprolinemelanocytemelanomamenmortalitymutation carriernovelnovel chemopreventionpeptide analogpeptidomimeticspre-clinicalpreventreceptorrepairedresponseskin color
项目摘要
Solar ultraviolet radiation (UV) is the main etiological factor for melanoma, the deadliest form of skin cancer,
and the fifth most diagnosed cancer in veterans. The incidence of melanoma is higher in veterans than in
civilians, particularly in individuals with light skin color and poor tanning ability. Over 65% of all veterans have
this phenotype. Deployment of millions of soldiers in geographical areas such as Iraq and Afghanistan
increases their risk for melanoma due to unavoidable daily excessive sun exposure without optimal protection.
Given the limitations of advanced therapeutic options for melanoma, it is important to focus on developing new
chemoprevention strategies to reduce its incidence. Our goal is to develop a melanoma prevention strategy
based on targeting the melanocortin 1 receptor (MC1R), the product of a bona fide melanoma predisposition
gene known to be a major regulator of human pigmentation and the response of melanocytes to solar UV. We
were the first to report the seminal findings that activation of the MC1R, a membrane-bound Gs protein-coupled
receptor expressed on melanocytes, by its agonist α-melanocyte stimulating hormone (α-melanocortin; α-MSH)
reduces UV-induced DNA damage by enhancing DNA repair and antioxidant capacities, in addition to
stimulating the synthesis of photoprotective eumelanin. Others have shown that expression of a loss-of-
function variant of MC1R is associated with increased UV signature mutations and the common somatic
V600E mutation in BRAF, that drive melanomagenesis. About 50% of all White Caucasians, including about 7
million veterans, are heterozygous carriers of a MC1R variant, a genotype associated with increased risk for
melanoma. These individuals will particularly benefit from our prevention strategy that will enhance the
activation of the MC1R. We have developed tetra- and tripeptide analogs of α-MSH that mimic the effects of
α-MSH on human melanocytes, and are stable and lipophilic, and unique in their high selectivity for the
MC1R. The cosmetic use of these peptides is covered by a published patent application. The tetrapeptides are
100 fold more potent, and the tripeptides are only 10 fold less potent than α-MSH in activating MC1R signaling
and its downstream effects in cultured human melanocytes. These peptides enhanced repair of UV-induced
DNA photoproducts, and increased pigmentation of cultured human skin substitutes (CSS) without any UV
exposure. These small peptides, unlike α-MSH, should not cause immunosuppression, since they lack
the COOH-terminal 11-13 amino acid residues (Lys-Pro-Val) of α-MSH that are responsible for its anti-
inflammatory and immunosuppressive effects. We propose that our tri- and tetrapeptide analogs of α-MSH
that are selective for the MC1R will be developed as topical agents to stimulate skin pigmentation and reduce
UV-induced DNA damage, in order to maintain the genomic stability of melanocytes, and therefore reduce the
risk for melanoma in veterans. Our Specific Aims are: I: To develop topical formulations of MC1R-selective
tetrapeptide and tripeptidepeptide, demonstrate their permeation through the epidermis, quantify their
concentrations in the skin layers, and validate their photoprotective effects on intact human skin or CSS in vitro
when applied topically. II. To test the effects of the two peptides on pre-clinical animal models, including
human CSS that will be grafted onto immunodeficient mice, and a miniature pig model with skin similar to that
of humans. Endpoints will include measurement of DNA damage, changes in pigmentation, proliferation and
apoptosis of keratinocytes and melanocytes. Blood samples will be obtained for preliminary pharmacokinetics
testing and tissue samples will be examined for gross toxicological effects. The outcome of this project should
advance us closer towards application for Investigational New Drug and conducting clinical trials.
太阳紫外线辐射(UV)是黑色素瘤的主要病因,黑色素瘤是最致命的皮肤癌,
项目成果
期刊论文数量(0)
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会议论文数量(0)
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ZALFA ABDEL-MALEK其他文献
ZALFA ABDEL-MALEK的其他文献
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{{ truncateString('ZALFA ABDEL-MALEK', 18)}}的其他基金
Vitiligo topical treatment applying a potent, highly selective MC1R agonist
使用强效、高选择性 MC1R 激动剂进行白癜风局部治疗
- 批准号:
10759768 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Targeting the Melanocortin 1 Receptor by Selective Small Analogs of α-Melanocortin for Melanoma Prevention
通过选择性α-黑皮质素小类似物靶向黑皮质素 1 受体预防黑色素瘤
- 批准号:
10474302 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Targeting the Melanocortin 1 Receptor by Selective Small Analogs of α-Melanocortin for Melanoma Prevention
通过选择性α-黑皮质素小类似物靶向黑皮质素 1 受体预防黑色素瘤
- 批准号:
10265379 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Melanoma prevention by MC1R selective small peptide analogs of alpha MSH
通过 MC1R 选择性 α MSH 小肽类似物预防黑色素瘤
- 批准号:
9105353 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Melanoma prevention by MC1R selective small peptide analogs of alpha MSH
通过 MC1R 选择性 α MSH 小肽类似物预防黑色素瘤
- 批准号:
8958319 - 财政年份:2015
- 资助金额:
-- - 项目类别:
How p16 and MC1R mutations synergistically exacerbate melanoma risk.
p16 和 MC1R 突变如何协同加剧黑色素瘤风险。
- 批准号:
8652005 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Impact of MC1R Functional Variants on the DNA Damage Response of Human Melanocyte
MC1R 功能变异对人黑素细胞 DNA 损伤反应的影响
- 批准号:
7730250 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Impact of MC1R Functional Variants on the DNA Damage Response of Human Melanocyte
MC1R 功能变异对人黑素细胞 DNA 损伤反应的影响
- 批准号:
8462256 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Signaling Pathways for UV-Induced Melanogenic Response
紫外线诱导的黑色素生成反应的信号通路
- 批准号:
7902757 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Impact of MC1R Functional Variants on the DNA Damage Response of Human Melanocyte
MC1R 功能变异对人黑素细胞 DNA 损伤反应的影响
- 批准号:
8274543 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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