Pro-melanomagenic role of Interferon-gamma: A paradigm shift

描述（由申请人提供）：候选人拥有生物化学和分子生物学博士学位，在使用小鼠模型进行基础癌症研究方面具有丰富的经验。在他的博士后研究期间，这位候选人产生了一种新的小鼠模型，该模型使人们对紫外线辐射（UV）如何导致黑色素瘤（最致命的皮肤癌形式）的发展有了新的认识。他已经做出了一个重要的发现，即干扰素（IFN）-γ，一种参与免疫功能并且通常被认为是抗肿瘤发生的信号蛋白，在某些情况下可能有助于UV诱导的黑素瘤的生长和进展。这项高影响力的研究为本申请中提出的研究奠定了基础。候选人的直接目标是阐明IFN-γ的促黑色素瘤作用的分子机制，并探索IFN-γ的抑制是否可用作抗黑色素瘤治疗和/或预防策略。从长远来看，候选人希望专注于紫外线诱导的黑色素瘤发生和进展的分子机制的描绘。工作环境：候选人目前是国家癌症研究所癌症生物学和遗传学实验室的博士后研究员，正在寻求学术或非营利研究机构的独立研究教师职位。他与世界一流的科学家团队建立了合作关系，他们拥有相关的专业知识，在整个项目中提供建议，确保及时得出结论和产生高影响力的结果。调研：该候选人提出了一个范式转移假说，即IFN-γ在UVB诱导的黑色素瘤发生中起促肿瘤发生作用。拟议的研究将阐明IFN-γ促黑色素瘤作用的分子机制，并将探索抑制IFN-γ通路是否是人类黑色素瘤的可行治疗和/或预防策略。在具体目标1中，将在IFN-γ敲除遗传背景下的UVB诱导的黑色素瘤发生小鼠模型中进行UV诱导的黑色素瘤发生实验，以检测黑色素瘤发生是否需要IFN-γ。具体目标2将使用人和小鼠黑素瘤细胞系阐明介导IFN-γ促黑色素瘤效应的IFN-γ信号传导的下游靶基因。将在人黑色素瘤细胞系和组织中验证结果的适用性。在Specifi Aim 3中，将验证和测试新型基于肽的IFN-γ抑制化合物在预防UVB诱导的黑色素瘤发生和治疗小鼠模型中已建立的黑色素瘤中的功效。预计从拟议研究中获得的结果将为预防和治疗人类黑色素瘤提供重要的新转化机会。

DESCRIPTION (provided by applicant): The candidate has a doctorate in Biochemistry and Molecular Biology with extensive experience in using mouse models to perform basic cancer research. During his postdoctoral fellowship, the candidate has generated a novel mouse model that has allowed new insights into how ultraviolet radiation (UV) may cause development of melanoma, the deadliest form of skin cancer. He has made an important discovery that interferon (IFN)-gamma, a signaling protein involved in immunological functions and conventionally thought to be anti-tumorigenesis, may under some circumstances aid the outgrowth and progression of UV- induced melanoma. This high-impact research has formed the basis for the research proposed in this application. The candidate's immediate goal is to elucidate the molecular mechanism(s) of the pro- melanomagenic role of IFN-gamma, and to explore whether inhibition of IFN-gamma could be used as an anti- melanoma therapeutic and/or preventive strategy. In the long-term, the candidate wants to focus on the delineation of the molecular mechanisms of UV-induced melanoma initiation and progression. Environment: The candidate is currently a postdoctoral research fellow in the Laboratory of Cancer Biology and Genetics at the National Cancer Institute, and is seeking an independent research faculty position in an academic or non-profit research institution. He has set up collaborations with a world-class team of scientists with relevant expertise to advise throughout this project, ensuring timely conclusion and high-impact outcome. Research: The candidate has proposed a paradigm-shifting hypothesis that IFN-gamma plays a pro- tumorigenic role in the context of UVB-induced melanomagenesis. The proposed research will elucidate the molecular mechanisms of the pro-melanomagenic effects of IFN-gamma, and will explore whether inhibition of IFN-gamma pathway is a viable treatment and/or preventive strategy for human melanoma. In Specific Aim 1, UV-induced melanomagenesis experiments will be performed in a mouse model of UVB-induced melanomagenesis in the IFN-gamma knockout genetic background to test whether IFN-gamma is required for melanomagenesis. Specific Aim 2 will elucidate the downstream target genes of IFN-gamma signaling that mediate the pro-melanomagenic effects of IFN-gamma, using both human and mouse melanoma cell lines. The applicability of the results will be validated in human melanoma cell lines and tissues. In Specifi Aim 3, novel peptide-based IFN-gamma inhibiting compounds will be validated and tested for their efficacy in preventing UVB-induced melanomagenesis and treating established melanomas in mouse models. It is anticipated that the results obtained from the proposed research will provide significant new translational opportunities for prevention and treatment of human melanoma.