Functional Characterization of Hmga2 in Lung Cancer Progression

说明： 转移导致大多数与癌症相关的死亡，然而许多分子决定因素和他们的 其作用机制尚不清楚。该提案详细介绍了职业发展计划和研究。 目的进一步加强蒙特温斯洛博士在癌症转移研究中的培训。而当 在K99的指导阶段，由泰勒·杰克博士监督，申请者将致力于 他的主要目标是将他的基因发现工作转变为功能验证。这个 Jack实验室和马萨诸塞州研究所的科赫癌症综合研究所 理工学院是进行这些研究的理想环境，因为它们将提供 成功所需的设备、设施和智力刺激。申请者的最终目标是 指导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，希望这些知识最终可能会影响人类健康。 这项拟议的研究主要建立在初步数据的基础上，这些数据揭示了对 同源盒转录因子Nkx2-1作为肺癌进展和转移的重要调节因子 转移。Nkx2-1调控基因的查询及肿瘤分期分析 研究表明，Nkx2-1可能通过抑制胚胎限制而抑制肿瘤 转录调节因子和细胞外基质的成分。拟议中的实验将 阐述这些因子在调节体外和肿瘤转移相关表型中的作用 体内自体肺腺癌模型的进展和转移。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。这个 这项建议的具体目的是：(1)确定Nkx2-1和Nkx2-1-受监管的相关性 基因与肺腺癌的进展；(2)询问候选基因在肺腺癌进展中的功能 建立小鼠自体肺腺癌模型；(3)检测HMGA2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.