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

描述(由申请人提供) 这项提议的目的是促进Michael Laiosa博士从一个有导师的博士后研究职位过渡到一名独立的学术研究科学家。为了追求建立独立性的目标，莱奥萨博士提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。这个小鼠模型将被用来确定T细胞急性淋巴细胞白血病(T-ALL)形成和发展的环境基础的潜在机制(S)。与公共健康相关的是，该模型将用于对饮食和化学预防药物白藜芦醇进行临床前评估，白藜芦醇有可能防止癌症风险较高的个人发生和/或复发T细胞白血病。此外，美国目前约有20.8万人患有白血病，每年约有2.2万人死于这种疾病。已确定了数十种白血病疾病的遗传风险因素，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，人类每天都会低水平地接触到这些化合物。了解环境因素如何影响白血病的发展和进展，不仅是我们知识上的一个重大缺口，而且将为莱奥萨博士提供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的一个新领域的额外培训。具体地说，这项提案将试图定义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。这项建议将确定TCDD激活芳香烃受体(AHR)如何通过测试以下三个特定目标潜在地调节Notch的活性：1)检验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、细胞周期调节和细胞凋亡调节的假说；2)测试AHR的表达和/或环境因素激活与激活的Notch“1相互作用”的假说；3)测试化学预防性药物白藜芦醇拮抗AHR依赖毒性和抑制T-ALL白血病发生的假说。

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.