Environmental Influence on T-Cell Leukemia: Role of Notch and AhR Signaling

环境对 T 细胞白血病的影响：Notch 和 AhR 信号传导的作用

• 批准号: 7660533
• 负责人: Michael D Laiosa
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660533
• 关键词: Acute T Cell Leukemia; Adult; Affect; Age; Apoptosis; Apoptotic; Aryl Hydrocarbon Receptor; BHLH Protein; Binding; Cancer Etiology; Cell Cycle Progression; Cell Cycle Regulation; Cell Lineage; Cell Proliferation; Chemicals; Child; Childhood; Childhood Leukemia; Complex; DNA biosynthesis; Data; Development; Diagnosis; Dioxins; Disease; Disease Progression; Elements; Enhancers; Environmental Exposure; Environmental Pollutants; Environmental Pollution; Environmental Risk Factor; Epidemiologic Studies; Exposure to; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Goals; Hour; Human; Immunotoxicology; Individual; Knowledge; Lead; Leukemia in Remission; Life; Ligands; Link; Malignant Neoplasms; Mentors; Microarray Analysis; Modeling; Mus; Mutation; Oncogenic; Organ; Patients; Play; Population; Positioning Attribute; Progressive Disease; Proteins; Public Health; Receptor Activation; Recurrence; Regulation; Regulator Genes; Research; Research Personnel; Resveratrol; Role; Sampling; Scientist; Signal Transduction; Staging; Stimulus; Survival Rate; T-Cell Development; T-Cell Leukemia; T-Lymphocyte; Testing; Tetrachlorodibenzodioxin; Thymocyte Development; Thymus Gland; Toxic effect; Training; Translating; Treatment Protocols; United States; Work; base; cancer risk; environmental agent; experience; genetic regulatory protein; genetic risk factor; improved; leukemia; notch protein; outcome forecast; pre-clinical; prenatal exposure; prevent; receptor expression; research clinical testing; self-renewal; thymocyte

DESCRIPTION (provided by applicant) The purpose of this proposal is to facilitate the transition of Dr. Michael Laiosa from a mentored postdoctoral research position to an independent academic research scientist. In pursuit of the goal of establishing independence, Dr. Laiosa has proposed to translate findings from human epidemiological studies to a murine model of dioxin-induced T-cell leukemia. This murine model will be used to determine the underlying mechanism(s) of the environmental basis for T-cell acute lymphoblastic leukemia (T-ALL) formation and progression. The relevance to public health is that this model will be employed for a pre-clinical evaluation of the dietary and chemopreventative agent resveratrol, which has the potential to prevent the initiation and/or recurrence of T-cell leukemia in individuals with elevated cancer risk. Moreover, approximately 208,000 people in the United States are currently living with leukemia and approximately 22,000 people a year will die from the disease. Dozens of genetic risk factors for leukemic diseases have been identified, and a number of environmental agents have been shown to increase cancer risk, including 2,3,7,8 -tetrachlordibenzo-pdioxin (TCDD) and dioxin-like compounds, which humans are exposed to at low levels on a daily basis. Understanding, how environmental factors affect the development and progression of leukemia not only represents a significant gap in our knowledge but will also provide Dr. Laiosa with additional training in a new field for him (leukemia) using his extensive experience in the field of thymocyte development and developmental immunotoxicology as a framework. Specifically, this proposal will attempt to define how TCDD interacts with mutations in the Notch protein potentially leading to T-ALL. Mutations in Notch have been identified in more than 70% of patients with T-ALL. This proposal will determine how TCDD activation of the Aryl hydrocarbon receptor (AHR) potentially modulates Notch activity by testing the following three specific aims: 1) test the hypothesis that during thymocyte development, ligand activation of the AHR synergizes with the Notch protein, modulating gene expression, cell cycle regulation, and apoptotic regulation; 2) test the hypothesis that AHR expression and/or activation by environmental agents interacts with activated Notch" 1 promoting T-leukemeogenesis; 3) test the hypothesis that the chemo-preventative agent resveratrol antagonizes AHR dependent toxicity and inhibits T-ALL leukemeogenesis.

描述（由申请人提供） 该提案的目的是促进Michael Laiosa博士从一个受指导的博士后研究职位过渡到一个独立的学术研究科学家。为了追求建立独立性的目标，Laiosa博士建议将人类流行病学研究的结果转化为二恶英诱导的T细胞白血病的小鼠模型。该小鼠模型将用于确定T细胞急性淋巴细胞白血病（T-ALL）形成和进展的环境基础的潜在机制。与公共卫生的相关性在于，该模型将用于饮食和化学预防剂白藜芦醇的临床前评估，白藜芦醇具有预防癌症风险升高的个体中T细胞白血病的开始和/或复发的潜力。此外，美国目前约有208，000人患有白血病，每年约有22，000人死于该疾病。已经确定了几十种白血病的遗传风险因素，一些环境因素已被证明会增加癌症风险，包括2，3，7，8-四氯二苯并二恶英（TCDD）和二恶英类化合物，人类每天都会接触到这些化合物。了解环境因素如何影响白血病的发展和进展，不仅代表了我们知识上的一个重大差距，而且还将为Laiosa博士提供一个新领域（白血病）的额外培训，利用他在胸腺细胞发育和发育免疫毒理学领域的丰富经验作为框架。具体来说，该提案将试图确定TCDD如何与可能导致T-ALL的Notch蛋白突变相互作用。 在超过70%的T-ALL患者中发现了Notch突变。本研究拟通过以下三个方面的研究来确定TCDD激活芳烃受体（AHR）如何潜在地调节Notch的活性：1）验证在胸腺细胞发育过程中，AHR的配体激活与Notch蛋白协同作用，调节基因表达、细胞周期调控和凋亡调控; 2）检验AHR表达和/或环境因子的活化与活化的Notch-1相互作用促进T-白血病发生的假设; 3）检验化学预防剂白藜芦醇拮抗AHR依赖性毒性并抑制T-ALL白血病发生的假设。