Epigenetic markers involved in colorectal cancer recurrence and metastases

描述(由申请者提供)：该指导职业奖概述了Ahuja博士在癌症生物学领域向科学独立过渡的五年培训计划。Ahuja博士提议扩大她的科学技能和知识，预计她将在本授权期结束时获得独立调查员的地位。阿胡贾博士将继续与表观遗传学专家贝林博士建立科学指导关系。她还将得到利奇博士的指导，利奇博士是胰腺发育生物学专家，也是一名外科医生，将提供宝贵的临床指导。在获奖期间，她得到了她所在部门的全力支持，至少保护了她75%的时间。Ahuja博士在Baylin博士的实验室里有实验室和办公室，完全沉浸在研究环境中。该实验室位于癌症研究大楼内， 约翰斯·霍普金斯大学拥有众多知名科学家，他们的工作环境有利于临床医生科学家的合作和支持。研究计划侧重于了解DNA甲基化在结直肠癌转移和复发中的作用，并了解其作为翻译标记物的适用性。表观基因沉默包括启动子相关CpG岛的异常DNA甲基化，是结直肠癌抑癌基因失活的中心机制。我们假设甲基化图谱作为结直肠癌复发的预后标志物具有巨大的潜力，并且甲基化图谱可能使结直肠癌的分子分期成为可能。为了验证这些假说，提出了以下目标：1)利用甲基化特征来预测早期结肠癌的复发。2)建立在结直肠癌转移过程中的甲基化改变，以寻找预测复发和转移的新标记物；3)建立结直肠癌的分子分期系统。这项研究将建立在令人振奋的初步结果的基础上，证明甲基化特征在预测复发方面的作用。此外，还将对结直肠癌发生的晚期事件进行系统的了解。相关性：结直肠癌是全世界和美国癌症死亡的主要原因。这项建议的长期目标是利用表观遗传学这一新兴领域的知识，建立预测结直肠癌复发高危患者的新标记物，并定义新的癌症治疗方法。

DESCRIPTION (provided by applicant): This mentored career award outlines a five-year training program for Dr. Ahuja's transition to scientific independence in the field of cancer biology. Dr. Ahuja proposes to expand her scientific skills and knowledge and it is expected that she would attain independent investigator status at the end of this award period. Dr. Ahuja will continue an established scientific mentorship with Dr. Baylin, an expert in epigenetics. She will also be mentored by Dr. Leach, an expert in pancreatic developmental biology and a fellow surgeon who will provide valuable clinical guidance. She has the full support of her Department to protect at least 75% of her time during the award period. Dr. Ahuja has laboratory and office space within Dr. Baylin's laboratory and is fully immersed in the research environment. The laboratory is located in the Cancer Research Buildings at Johns Hopkins and has access to many established scientists with an environment that favors collaboration and support of clinician scientists. The research plans focuses on understanding the role of DNA methylation in colorectal cancer metastases and recurrence and understand its applicability as translational markers. Epigenetic gene silencing involving aberrant DNA methylation of promoter-associated CpG islands functions as a central mechanism of inactivation of tumor-suppressor genes in colorectal cancer. We hypothesize that methylation profiles hold enormous potential as prognostic markers for recurrence in colorectal cancer and methylation profiles may allow molecular staging of colorectal cancer. In order to test these hypotheses, the following aims are proposed: 1) To utilize methylation profiles to predict recurrence in early-stage colon cancers. 2) To establish the methylation changes that underlie the process of metastasis in colorectal cancers in order to identify novel markers for predicting recurrence and metastases 3) To develop a molecular staging system for colorectal cancer. The research will build on exciting preliminary results demonstrating the utility of methylation profiles to predict recurrence. In addition, a systematic understanding of late events in colorectal carcinogenesis will be performed. Relevance: Colorectal cancer is a leading cause of cancer death worldwide and in the United States. The long-term goal of this proposal is to utilize knowledge of the newly emerging field, termed epigenetics, to establish novel markers for predicting patients at high-risk for colorectal cancer recurrence and to define novel cancer treatments.