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为当代医生带来了巨大的机遇和挑战。该K24的发展目标旨在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。申请人是一名处于职业生涯中期的临床科学家，其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。该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得到广泛认可。他在马萨诸塞州总医院（MGH）创立并指导了一个充满活力的黑色素瘤遗传学项目，在哈佛大学建立了一个丰富的遗传黑色素瘤登记处，其中包括来自世界各地的250多个黑色素瘤家庭，并领导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-一个致力于黑色素瘤患者护理的临床单位；这种多学科的基础设施为将基础发现带到床边提供了独特的机会。申请人曾指导许多医学院学生、专科和亚专科学员和博士后正确开展以患者为导向的分子研究。导师计划包括一系列核心培训目标：(1)发展学术成功所需的技能设施，包括执行健全科学基础的能力，以连贯性和说服力撰写拨款和手稿，并提供简洁而令人信服的陈述，(2)批判性地评估科学的设计和解释，(3)有效地构建科学方法，从技术到实验到项目，最后到计划，(4)在科学社区的背景下成熟。这些将通过执行4个广泛的科学目标来实现：(1)创建一个强大的模型（称为MelaPRO）来估计CDKN2A/CDK4突变载体概率；(2)在缺乏CDKN2A/CDK4改变的高风险家庭中识别rb通路基因的编码变异；(3)开发一个灵活、准确、高通量的平台来评估CDKN2A/CDK4/MC1R基因型；(4)设计一种新的功能检测方法来检测患者衍生的黑素皮质素-1受体（MC1R）基因变异。通过拟议的K24中期职业发展奖，申请人将能够为黑色素瘤患者开发几种有形产品，扩展自己在变异组学重要新兴领域的知识，最重要的是，找到必要的时间指导学员和初级教员，并维持一个富有成效的研究实验室。

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.