Mechanism Based Chemoprevention of Cancer

描述(申请人提供)：此申请的主要目的是寻求全力支持我成为一名癌症预防领域的独立调查员。两个主要目标是：(1)建立我在癌症预防领域的独立研究人员的职业生涯，(2)在了解它们的作用机制的基础上，在开发有用的化学预防新剂方面做出研究贡献。我的短期目标包括设计新的药物，研究这些新药物的作用机制，以及在临床前研究中研究新的药物。来自达特茅斯医学院、达特茅斯学院和诺里斯·科顿癌症中心的合作者，以及一群杰出的顾问，将帮助我在有机化学、高级分子生物学、病理学和临床研究设计等癌症预防领域拓宽我的广度和增加我的知识深度。在此提出的近期研究计划有三个具体目标：1)在我的分子生物学实验室阐明新的合成三萜类化合物的构效关系；2)研究新的化学预防药物的分子和细胞作用机制。基于对三萜类化合物的初步研究，特定的分子靶点将被研究如下：炎症基因，如iNOS和COX-2，特定的核受体，如PPAR-γ及其相关的共激活和共抑制因子，以及转化生长因子-β受体和Smad信号系统；以及3)在与人类疾病相关的动物模型中评估新的化学预防药物。这样的研究将导致对我的工作进行最有效的临床翻译。新的化学预防药物将在两种乳腺癌模型中进行测试，即ER阳性(NMU诱导的大鼠乳腺癌模型)和ER阴性(转基因小鼠模型)，以及偶氮甲烷诱导的大鼠结肠癌模型。因此，我研究的短期目标是开发新的化学预防药物，其使用可以在临床上得到验证。我的长期目标是成为一名独立的调查员，能够对整个过程做出贡献，使基础科学知识有效地预防男性和女性的癌症。

DESCRIPTION (provided by applicant): The main objective of this application is to seek full support for me to become an independent investigator in the field of cancer prevention. Two primary goals are: (1) to establish my career as an independent researcher in the field of cancer prevention, and (2) to make a research contribution in developing useful new agents for chemoprevention, based on understanding their mechanisms of action. My short-term goals involve the design of new agents, studying mechanisms of action of these new agents, and investigating new agents in preclinical studies. Collaborators from Dartmouth Medical School, Dartmouth College, and Norris Cotton Cancer Center, as well as a distinguished group of consultants, will help me to widen the breadth and increase the depth of my knowledge in the field of cancer prevention areas as diverse as organic chemistry, advanced molecular biology, pathology, and clinical study design. The immediate research plan proposed here has three Specific Aims: 1) to elucidate structure-activity relationships of new synthetic triterpenoids in my molecular biology laboratory; 2) to study molecular and cellular mechanisms of action of new chemopreventive agents. Based on preliminary studies with triterpenoids, specific molecular targets will be investigated as follows: inflammatory genes such as iNOS and COX-2, specific nuclear receptors, such as PPAR-gamma and its associated co-activators and co-repressors, and the TGF-beta receptor and Smad signaling system; and 3) to evaluate new chemopreventive agents in animal models relevant to human disease. Such studies will lead to the most effective clinical translation of my work. New chemopreventive agents will be tested in two models of breast cancer, namely ER positive (NMU-induced breast cancer model in rats) and ER negative (a transgenic mouse model), as well as the azoxymethane-induced colon cancer model in rats. Thus, the short-term goal of my research is to develop new chemopreventive agents whose use can be clinically validated. My long-term goal is to become an independent investigator who can contribute to the entire process of making basic scientific knowledge effective in preventing cancer in men and women.