Functional Characterization of Hmga2 in Lung Cancer Progression

产品说明： 转移导致大多数癌症相关的死亡，但许多分子决定因素及其作用机制， 其作用机制尚不清楚。该提案详细说明了职业发展计划和研究 目的是在Monte温斯洛博士研究癌症转移期间进一步培训他。而 在K99的指导阶段，由泰勒杰克斯博士监督，申请人将致力于 他把时间花在了将基因发现工作转变为功能验证的主要目标上。的 杰克斯实验室和科赫综合癌症研究所在马萨诸塞州研究所 技术是进行这些研究的理想环境，因为它们将提供所有 成功所需的设备、设施和智力刺激。申请人的最终目标是 指导一个学术研究实验室，解决有关生物学和机械学的问题。 控制转移的细节，希望这些知识可以及时影响人类健康。 这项拟议中的研究在很大程度上建立在初步数据的基础上，这些数据揭示了 同源框转录因子Nkx 2 -1作为肺肿瘤进展的重要调节因子， 转移Nkx 2 -1调节基因的询问和肿瘤在特定阶段的分析 研究表明Nkx 2 -1可能通过抑制胚胎限制性的 转录调节因子和细胞外基质成分。拟议的实验将 阐明这些因子在体外和肿瘤转移相关表型中的调节作用 在体内原位肺腺癌模型中的进展和转移。这些 实验将有助于我们理解肺腺癌的分子基础， 向恶性肿瘤的进展与国家癌症研究所的使命一致。的 本提案的具体目的是：（1）确定Nkx 2 -1和Nkx 2 -1调节的相关性 基因对肺腺癌进展的影响;（2）询问候选基因在肺腺癌进展中的功能。 原位肺腺癌小鼠模型;（3）确定Hmga 2缺失对肿瘤的影响 进展和转移。

DESCRIPTION: Metastasis leads to most cancer-related deaths, yet many of the molecular determinants and their mechanisms of action remain unknown. This proposal details a career development plan and research objectives to further the training of Dr. Monte Winslow during his studies on cancer metastasis. While supervised by Dr. Tyler Jacks during the mentored phase of the K99, program the applicant will devote his time to the major objective of transitioning his gene-discovery work into functional validation. The Jacks laboratory and the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology are the ideal environment in which to conduct these studies, as they will provide all equipment, facilities and intellectual stimulation required for success. The applicant's ultimate goal is to direct an academic research laboratory addressing questions regarding the biology and mechanistic details that control metastasis, with the hope that this knowledge may, in time, impact human health. The proposed research builds heavily on preliminary data that uncovered down-regulation of the homeobox transcription factor Nkx2-1 as an important regulator of lung tumor progression and metastasis. Interrogation of Nkx2-1 regulated genes and analysis of tumors at defined stages of development indicate that Nkx2-1 may constrain tumors by repressing embryonically-restricted transcriptional regulators and components of the extracellular matrix. The proposed experiments will address the role of these factors in regulating metastasis-associated phenotype in vitro and tumor progression and metastasis in an autochthonous lung adenocarcinoma model in vivo. These experiments will contribute to our understanding of the molecular underpinning of lung adenocarcinoma progression towards malignancy consistent with the mission of the National Cancer Institute. The Specific Aims of this proposal are to: (1) Determine the relevance of Nkx2-1 and Nkx2-1-regulated genes to lung adenocarcinoma progression; (2) Interrogate the function of candidate genes in an autochthonous lung adenocarcinoma mouse model; (3) Determine the effect of Hmga2 loss on tumor progression and metastasis.