Molecular Risk Assessment in Hereditary Melanoma

描述(由申请人提供)：遗传学和基因组学的快速发展给当代医生带来了巨大的机遇和挑战。K24的开发目标是培训和指导以患者为导向的内科科学家进行创新研究，将分子遗传学转化为分子医学。申请者是一名职业生涯中期的临床科学家，他的研究项目侧重于基因组科学在遗传性黑色素瘤患者管理中的应用。这位候选人因其在黑色素瘤易感性和进展的遗传学方面的贡献而被广泛认可。他在马萨诸塞州总医院(MGH)创建并指导了充满活力的黑色素瘤遗传学计划，在哈佛大学建立了一个丰富的遗传性黑色素瘤登记处，拥有来自世界各地的250多个黑色素瘤家庭，并领导着威尔曼光医学中心的皮肤癌遗传学实验室和MGH黑色素瘤和色素病变中心-致力于黑色素瘤患者护理的临床单位；这个多学科的基础设施提供了独特的机会，将基本发现带到床边。申请人曾指导过许多医学生、专科和专科实习生以及博士后研究员如何正确地进行以患者为中心的分子研究。导师计划包括一套核心培训目标：(1)发展学术成功所需的技能，包括执行健全的科学基础知识的能力，以连贯和有说服力的方式撰写补助金和手稿，并提供简洁和令人信服的陈述，(2)为设计和解释对科学进行批判性评估，(3)有效地将科学方法从技术到实验再到项目再到计划，以及(4)在科学界的背景下成熟。这些目标将通过执行四个广泛的科学目标来实现：(1)创建稳健的模型(称为MelaPRO)来估计CDKN2A/CDK4突变携带者的概率，(2)在缺乏CDKN2A/CDK4改变的高危家庭中识别RB途径基因的编码变体，(3)开发一个灵活、准确、高通量的平台来评估CDKN2A/CDK4/MC1R基因类型，以及(4)设计新的功能分析方法来分析患者来源的黑素皮质素-1受体(MC1R)基因的变异。通过拟议的K24职业中期发展奖，申请者将能够为黑色素瘤患者开发几种有形的产品，扩大自己对重要的新兴变异组学领域的知识，最重要的是，找到必要的时间来指导受训者和初级教师，并维持一个富有成效的研究实验室。 公共卫生相关性：人类基因组计划点燃的科学势头为医学创造了前所未有的机遇和挑战。在皮肤黑色素瘤中，就像在许多其他领域一样，一个不断扩大的鸿沟将坐在台上的分子科学家和床边的临床医生/研究人员分开。这一K24应用程序旨在指导和培训下一代以患者为导向的内科科学家，以弥合这一差距，并将基因发现带给受黑色素瘤影响的个人和家庭。

DESCRIPTION (provided by applicant): Rapid gains in genetics and genomics pose both great opportunities and challenges for the contemporary physician. The developmental goals of this K24 are intended to train and mentor patient-oriented physician scientists to conduct innovative research that will transform molecular genetics into molecular medicine. The applicant is a mid-career clinician-scientist whose investigational program focuses on applications of genomic science to the management of hereditary melanoma patients. The candidate is widely recognized for his contributions in the genetics of melanoma predisposition and progression. He founded and directs a vibrant Melanoma Genetics Program at the Massachusetts General Hospital (MGH), established a rich Hereditary Melanoma Registry at Harvard with over 250 melanoma families from throughout the world and leads both the Skin Cancer Genetics Laboratory in the Wellman Center for Photomedicine and the MGH Melanoma and Pigmented Lesion Center- a clinical unit dedicated to the care of melanoma patients; this multidisciplinary infrastructure provides unique opportunities to bring basic discoveries to the bedside. The applicant has mentored many medical students, specialty and subspecialty trainees and postdoctoral fellows in the proper conduct of patient-oriented molecular research. The mentorship plan includes a set of core training objectives: (1) to develop facility in skills required for academic success including the ability to execute the fundamentals of sound science, to write grants and manuscripts with coherence and cogency and to deliver a concise and convincing presentation, (2) to critically evaluate science for design and interpretation, (3) to effectively frame the scientific method from techniques to experiments to projects and finally to programs and (4) to mature within the context of a scientific community. These will be achieved through the execution of 4 broad scientific Aims: (1) create a robust model (termed MelaPRO) to estimate CDKN2A/CDK4 mutation carrier probability, (2) identify coding variants in RB-pathway genes in high-risk families lacking CDKN2A/CDK4 alterations (3) develop a flexible, accurate, high-throughput platform to assess CDKN2A/CDK4/MC1R genotypes and (4) devise novel functional assays for patient-derived variants in the melanocortin-1-receptor (MC1R) gene. Through the proposed K24 mid-career development award, the applicant will be able to develop several tangible products for the melanoma patient, to expand his own knowledge of important emerging area of variomics and, most importantly, to find the necessary time to mentor trainees and junior faculty and sustain a productive research laboratory. PUBLIC HEALTH RELEVANCE: The scientific momentum ignited by the Human Genome Project has created unprecedented opportunities and challenges for medicine. In cutaneous melanoma, as in many other fields, an enlarging gulf divides the molecular scientist at the benchside and the clinician/researcher at the bedside. This K24 application is aimed at mentoring and training the next generation of patient-oriented physician-scientists to bridge this gap and to bring genetic discoveries to individuals and families affected by melanoma.