Regulation of Colon Cancer by AIM2

AIM2 对结肠癌的调节

• 批准号: 9753995
• 负责人: Justin Ethan Wilson
• 金额: $ 15.95万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753995
• 关键词: AIM2 gene; AKT inhibition; Address; Animal Model; ApcMin/+ mice; Apoptosis; Area; Binding; CRISPR/Cas technology; Cancer Etiology; Cancer Immunology Science; Cancerous; Canes; Cell Proliferation; Cell Signaling Process; Cell Survival; Cells; Cessation of life; Clinical; Clinical Research; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Comprehensive Cancer Center; Core Facility; DNA; DNA Binding; DNA Binding Domain; DNA-dependent protein kinase; Development; Disseminated Malignant Neoplasm; Epithelial Cells; Family member; Gene Expression; Genes; Germ-Free; Goals; Growth; Human; Immune; Immunologic Receptors; In Vitro; Inflammasome; Interleukin-1 beta; Interleukin-18; K22 Award; Laboratories; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of large intestine; Measures; Mediating; Microbe; Modeling; Multiprotein Complexes; Mus; Neoplasm Metastasis; North Carolina; Organ; Organoids; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphorylation; Play; Polyps; Process; Recombinants; Regulation; Reporting; Research; Research Personnel; Role; Sampling; Secondary to; Signal Pathway; Signal Transduction; Study models; Survival Rate; System; Testing; Tissues; Training; Transplantation; Treatment Factor; Tumor Suppressor Proteins; United States; Universities; Woman; Work; adenoma; cancer biomarkers; cancer cell; cancer initiation; cancer type; cell motility; colon cancer treatment; combat; ds-DNA; experimental study; gene induction; gut microbiome; gut microbiota; in vivo; inhibitor/antagonist; insight; men; metastatic colorectal; microbial; microbiome; microbiome sequencing; microbiota; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutics; personalized strategies; prevent; protein kinase inhibitor; response; sensor; tenure track; tumor; tumor xenograft; tumorigenesis

DESCRIPTION (provided by the applicant) Colorectal cancer is second leading cause of cancer-related deaths among men and women in the United States, with metastasis to secondary organs (e.g., liver) playing a major role in patient mortality. Patients with metastatic, or stage IV, colon cancer display a 5 year survival rate of only 11%. Recent clinical and gene profiling studies indicate that a loss of Absent in Melanoma 2 (AIM2) expression in colon tumors is highly correlated with stage IV colon cancer and reduced patient survival. AIM2 is a cytosolic innate immune sensor that forms a multi-protein complex termed the inflammasome following binding of double-stranded DNA. I have recently reported that AIM2 suppresses colon cancer development independently of its inflammasome function by limiting the uncontrolled replication of colonic epithelial cells by acting as a checkpoint of Akt-mediated survival. Mechanistically, AIM2 suppresses Akt activity by targeting the PI3K family member DNA-dependent protein kinase (DNA-PK). Although DNA-PK activation and expression is reportedly elevated in colon tumors, and DNA-PK promotes Akt activation, cell survival and metastatic gene profiles, the function of DNA-PK during colon cancer pathogenesis is largely understudied. In addition, AIM2 has been suggested to limit tumorigenesis by regulating the composition of the intestinal microbiota, yet there is no direct evidence for this, and it is unknown if microbiota-derived DNA facilitates AIM2's tumor suppressor function or what AIM2-related factors are responsible for limiting tumorigenesis. In this proposal, I will test the hypothesis that AIM2 restricts cancer initiation and metastasis by limiting Akt and DNA-PK activation in response to the microbiota using the following specific aims: 1) Determine the functional requirement of DNA binding to AIM2 during the suppression of cancer-relevant pathways in vitro; 2) Assess the ability of AIM2 to limit DNA-PK-mediated colon cancer development and metastasis in vivo; and 3) Elucidate the mechanism by which AIM2 responds to and regulates the intestinal microbiota to limit colon cancer. This proposal builds upon my prior work that includes a strong background in cell signal transduction, intestinal microbiome profiling and animal models of colon cancer initiation while working in the laboratory of Jenny P-Y Ting at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. With additional technical assistance and core facility support from my collaborators, this K22 award will provide critical training in in vitro primary colon organoid culture systems, Crispr/Cas9 gene editing, mouse models of spontaneous tumorigenesis and metastasis, gene expression and signal transduction profiling of human cancer tissue and manipulation of the microbiome to target cancer, which are required to achieve my long-term goal of becoming an established tenured-track principle investigator in the area of Cancer Immunology. The proposed research will lead to a greater understanding of how the tumor suppressor AIM2 limits tumorigenesis and may lead to the development of novel therapeutics for the treatment of multiple cancers.

描述（由申请人提供）结直肠癌是癌症相关死亡的第二大原因 在美国的男性和女性中，转移到次要器官（例如，肝）演奏一个主要的 患者死亡率的作用。转移性或IV期结肠癌患者的5年生存率仅为 百分之十一最近的临床和基因分析研究表明，黑色素瘤2（AIM 2）表达缺失， 在结肠肿瘤中，与IV期结肠癌和降低的患者存活率高度相关。AIM 2是一种细胞溶质 一种先天免疫传感器，在结合 双链DNA我最近报道说，AIM 2抑制结肠癌的发展独立 通过限制结肠上皮细胞的不受控制的复制， Akt介导的生存检查点。从机制上讲，AIM 2通过靶向PI 3 K家族抑制Akt活性 成员DNA依赖性蛋白激酶（DNA-PK）。尽管据报道DNA-PK的激活和表达是由 在结肠肿瘤中升高，DNA-PK促进Akt活化，细胞存活和转移基因谱， DNA-PK在结肠癌发病机制中的功能在很大程度上尚未得到充分研究。此外，AIM 2还 建议通过调节肠道微生物群的组成来限制肿瘤发生，但没有直接的 目前还不清楚微生物来源的DNA是否促进了AIM 2的肿瘤抑制功能， AIM 2相关因素是什么，负责限制肿瘤发生。在这个建议中，我将测试 AIM 2通过限制Akt和DNA-PK激活来限制癌症发生和转移的假说 使用以下具体目标响应微生物群：1）确定 在体外抑制癌症相关途径期间DNA与AIM 2的结合; 2）评估AIM 2的能力， 限制DNA-PK介导的结肠癌体内发展和转移;和3）阐明其机制 AIM 2通过这种方式响应并调节肠道微生物群以限制结肠癌。这一建议建立 基于我之前的工作，包括细胞信号转导，肠道微生物组分析， 和结肠癌发病的动物模型，同时在Jenny P-Y Ting的实验室工作， 位于查佩尔山的北卡罗来纳州大学Lineberger综合癌症中心。与附加 技术援助和核心设施的支持，这个K22奖将提供关键的培训 在体外原代结肠类器官培养系统中，Crispr/Cas9基因编辑，自发性结肠癌小鼠模型， 肿瘤发生和转移，人癌组织的基因表达和信号转导谱， 操纵微生物组以靶向癌症，这是实现我的长期目标所必需的， 在癌症免疫学领域建立了终身跟踪的主要研究者。拟议研究 这将有助于更好地了解肿瘤抑制因子AIM 2如何限制肿瘤发生，并可能导致 用于治疗多种癌症的新疗法的开发。