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

描述（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有丰富的经验。在他的博士后研究期间，这位候选人建立了一种新的小鼠模型，为紫外线辐射（UV）如何导致黑色素瘤（最致命的皮肤癌）的发展提供了新的见解。他有一个重要的发现，干扰素(IFN)- γ，一种参与免疫功能的信号蛋白，通常被认为是抗肿瘤的，在某些情况下可能有助于紫外线诱导的黑色素瘤的生长和进展。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的抑制是否可以用作抗黑色素瘤治疗和/或预防策略。从长远来看，候选人希望专注于描述紫外线诱导的黑色素瘤发生和发展的分子机制。环境：目前为美国国家癌症研究所癌症生物学与遗传学实验室博士后，寻求学术或非营利研究机构的独立研究岗位。他与具有相关专业知识的世界级科学家团队建立了合作关系，在整个项目中提供建议，确保及时得出结论并取得高影响力的成果。研究：候选人提出了一个范式转换的假设，即ifn - γ在uvb诱导的黑色素瘤形成中起着促瘤作用。该研究将阐明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Specific Aim 1中，我们将在ifn - γ敲除遗传背景下uvb诱导的黑色素瘤小鼠模型中进行紫外线诱导的黑色素瘤发生实验，以测试黑色素瘤发生是否需要ifn - γ。特异性目的2将阐明ifn - γ信号的下游靶基因，介导ifn - γ的促黑色素瘤效应，使用人类和小鼠黑色素瘤细胞系。结果的适用性将在人类黑色素瘤细胞系和组织中得到验证。在specific Aim 3中，新的基于肽的ifn - γ抑制化合物将在小鼠模型中验证和测试其在预防uvb诱导的黑色素瘤形成和治疗已建立的黑色素瘤方面的功效。预计从拟议的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.