Elucidating dietary fructose and alcohol interactions during liver cancer development

项目总结/摘要 这一NIAAA R 01补充的主要目的是装备米兰达洛佩斯女士，一个代表性不足， 研究生候选人，与必要的技能和知识，成为一个熟练和独立的 科学家在完成她提出的关于破译酒精/果糖机制的研究项目时， 诱导的肝细胞癌（HCC），是母体R 01奖的自然延伸。张哲顺博士 首席导师和共同导师Dequina Nicholas博士拥有必要的熟练程度和知识， 为她的项目完成和职业发展提供最佳的共同指导。具体地说， 博士Jang在营养学和癌症生物学方面有专长，Nicholas博士在免疫学方面有专长， 在指导少数族裔学生方面有丰富的经验。另外，为了确保洛佩斯女士的事业 为了发展，我们招募了两名资深教师担任她的指导委员会成员。期间 多样性补充期间，洛佩斯女士将进行实验，以确定特定脂质途径的作用 酒精/果糖诱导的肝癌（候选目标1）。她还将确定免疫调节是否 参与HCC肿瘤生长（候选目标2）。这两个目标都是母公司目标1的自然延伸 奖项：“果糖和酒精是否以及如何协同增加HCC风险”。虽然抗病毒治疗 已经证明有效预防病毒相关的HCC，癌症的起源现在正在从病毒转变为病毒 肝炎到代谢紊乱源于生活方式的选择，包括非酒精和酒精 脂肪性肝炎在父母奖中，我们假设果糖将酒精的代谢命运转向 通过诱导乙酰辅酶A合成酶2（ACSS 2）产生致癌代谢物，ACSS 2是一种细胞溶质酶， 将乙酸分解代谢为乙酰辅酶A。在目标1中，我们的目标是确定果糖和酒精 协同增加HCC风险。在目标2中，我们的目标是确定ACSS 2抑制和/或肠 微生物群耗竭抑制果糖和酒精诱导的HCC。在家长补助金的目标1中，我们 通过我们无偏见的非靶向代谢组学发现，酒精/果糖诱导的HCC显示出深刻的 极长链多不饱和脂肪酸（VLC-PUFA）的积累。血液VLC-PUFA 与HCC负荷密切相关，这表明使用血清VLC-PUFA作为HCC负荷的令人兴奋的可能性。 诊断标志物VLC-PUFA由VL 2（延长极长链脂肪酸蛋白2）合成， 我们发现在肿瘤中，CD 3VL 2蛋白的表达要高出3倍。最近，VLC-PUFA已显示出抑制 树突状细胞分化和减少细胞毒性T细胞。因此，洛佩斯先生将决定是否阻止 HPLC-VL 2抑制酒精/果糖诱导的HCC以及VLC-PUFA介导的免疫抑制是否 HCC进展的关键潜在机制。当她进行拟议的研究时，她将收到 广泛的培训，包括发展实验技术的专业知识，培养研究 独立性，磨练她的科学沟通技巧，并掌握granecraft的艺术，等等。

PROJECT SUMMARY/ABSTRACT The primary objective of this NIAAA R01 Supplement is to equip Ms. Miranda Lopez, an underrepresented graduate student candidate, with the skills and knowledge necessary to become a proficient and independent scientist while completing her proposed research project on deciphering mechanisms of alcohol/fructose- induced hepatocellular carcinoma (HCC), a natural extension of the parent R01 award. Dr. Cholsoon Jang, the lead mentor, and Dr. Dequina Nicholas, the co-mentor, possess the requisite proficiency and knowledge to offer an optimal co-mentorship for both the accomplishment of her project and her career growth. Specifically, Dr. Jang has expertise in nutrition and cancer biology and Dr. Nicholas has expertise in immunology and has plenty of experience in mentoring underrepresented minority students. Further, to ensure Ms. Lopez's career development, we have enlisted two senior faculty members to serve on her mentoring committee. During the diversity supplement period, Ms. Lopez will perform experiments to determine the role of specific lipid pathway in alcohol/fructose-induced HCC (Candidate Aim 1). She will also determine whether immunomodulation is involved in HCC tumor growth (Candidate Aim 2). Both aims are a natural extension of Aim 1 of the parent award: “whether and how fructose and alcohol synergistically increase HCC risk”. Although antiviral treatment has proven effective in preventing virus-associated HCC, the origin of the cancer is now transitioning from viral hepatitis to metabolic disorders that stem from lifestyle choices, including non-alcoholic and alcoholic steatohepatitis. In the parent award, we hypothesized that fructose shifts the metabolic fate of alcohol toward carcinogenic metabolite production via induction of acetyl-CoA synthetase 2 (ACSS2), a cytosolic enzyme that catabolizes acetate to acetyl-CoA. In Aim 1, we aim to determine whether and how fructose and alcohol synergistically increase HCC risk. In Aim 2, we aim to determine whether ACSS2 inhibition and/or gut microbiota depletion suppresses fructose and alcohol-induced HCC. In Aim 1 of the parent grant, we discovered, by our unbiased untargeted metabolomic, that alcohol/fructose-induced HCC showed a profound accumulation of very long-chain polyunsaturated fatty acids (VLC-PUFA). Furthermore, blood VLC-PUFA strongly correlates with HCC burden, suggesting an exciting possibility of using serum VLC-PUFA as an HCC diagnostic marker. VLC-PUFA are synthesized by ELOVL2 (elongation of very long chain fatty acids protein 2), and we found that ELOVL2 proteins are 3-fold higher in tumors. Recently, VLC-PUFA has been shown to inhibit dendritic cell differentiation and reduce cytotoxic T cells. Therefore, Mr. Lopez will determine whether blocking ELOVL2 suppresses alcohol/fructose-induced HCC and whether VLC-PUFA-mediated immune suppression is the key underlying mechanisms of HCC progression. As she undertakes the proposed research, she will receive a broad range of training, including developing expertise in experimental techniques, cultivating research independence, honing her scientific communication skills, and mastering the art of grantsmanship, among others.