Science Leadership and Integration

描述（由申请人提供）：该项目将利用小鼠遗传学来测试实施人类癌症个性化药物所需的概念和方法。这将需要在人类癌症联盟（MMHCC）的小鼠模型内以及与其他NCI资助的组织一起进行联合研究，对癌症易感性、进展和治疗反应中的遗传背景和基因表达网络进行系统遗传学分析。基于系统的方法的价值已经从肥胖和糖尿病易感性的小鼠研究中得到了证明，其中正常组织中的基因表达网络揭示了反映潜在易感性的信号通路，以及作为可行治疗靶点的信号枢纽。对皮肤癌小鼠模型的类似研究已经确定了控制组织结构和功能的分层网络，并为导致皮肤肿瘤易感性的机制提供了新的见解。这些综合系统方法在癌症中的应用对MMHCC所追求的所有研究领域都有重大影响。该项目将包括核心项目，其目的是构建来自种间回交小鼠和来自协作杂交的R1系的组织的组合单核苷酸多态性（SNP）和基因表达数据的可浏览数据库。这样的数据库对于癌症易感性和耐药性集群中的群体以及MMHCC和其他NCI资助的机构中的群体都是非常宝贵的。来自相同动物的组织库将提供给MMHCC成员，用于在蛋白质水平上研究基因表达的遗传控制。将在癌症易感性和耐药性主题内设立试点项目，使用相同的遗传方法，使用代表人类癌症主要形式的不同小鼠模型研究肿瘤易感性。进一步的目标是研究生殖系多态性和癌症检测，进展和治疗反应中的体细胞事件之间的相互作用。这些目标与路线图倡议基本重叠，特别是与综合癌症生物学计划（ICBP），卓越研究专业计划（SPORE）计划，早期检测研究网络（EDRN）和癌症家庭登记（CFR）的目标。每个项目的代表都为这种比较小鼠-人类遗传学方法提供了支持材料，以分析癌症易感性的多个方面。

DESCRIPTION (provided by applicant): This project will exploit mouse genetics to test the concepts and approaches that will be required to implement personalized medicine for human cancer. This will require joint studies, both within the mouse models of human cancer consortium (MMHCC) and together with other NCI-funded organizations, of systems genetics analysis of genetic background and gene expression networks in cancer susceptibility, progression and therapeutic responses. The value of systems-based approaches has been demonstrated from mouse studies of susceptibility to obesity and diabetes, in which the gene expression networks in normal tissues have revealed signaling pathways that reflect underlying susceptibility, as well as signaling hubs that are viable therapeutic targets. Similar studies of mouse models of skin cancer have identified hierarchical networks that control tissue structure and function, and provided novel insights into mechanisms that lead to skin tumor susceptibility. The application of these integrative systems approaches to cancer has major implications for all of the areas of research being pursued by the MMHCC. This project will include a Core Project, the purpose of which is to construct a browsable database of combined single nucleotide polymorphisms (SNPs) and gene expression data from tissues from interspecific backcross mice and from the Rl lines of the Collaborative Cross. Such a data base would be invaluable both for groups in the Cancer Susceptibility and Resistance cluster, but also more generally within the MMHCC and in other NCI-funded bodies. A tissue bank from the same animals will be available to members of the MMHCC for investigations of the genetic control of gene expression at the protein level. Pilot projects will be set up within the cancer susceptibility and resistance theme to use the same genetic approaches to investigate tumor susceptibility using different mouse models that represent the major forms of human cancer. A further goal is to investigate the interplay between germline polymorphisms and somatic events in cancer detection, progression and treatment responses. These aims overlap substantially with the Roadmap initiative, and in particular with the goals of the Integrated Cancer Biology Program (ICBP), the Specialized Programs of Research Excellence (SPORE) program, the Early Detection Research Network (EDRN) and the Cancer Family Registry (CFR). Representatives of each of these programs have provided supporting materials for this comparative mouse-human genetic approach to analysis of multiple aspects of cancer susceptibility.