Diversity Supplement Support for a Graduate Student Training in the Studies of HDAC11

为 HDAC11 研究研究生培训提供多样性补充支持

• 批准号: 10380445
• 负责人: Rong Li
• 金额: $ 8.18万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380445
• 关键词: Acylation; Adipose tissue; Adult; Affect; Attenuated; Body fat; Brown Fat; Cancer Biology; Cancer Model; Cell Line; Cell Proliferation; Cellular Metabolic Process; Chronic Disease; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Deacetylation; Diglycerides; Disease; Drug resistance; Event; Functional disorder; HDAC11 gene; Healthcare; High Fat Diet; Homeostasis; Immune; Infiltration; Interferons; Knowledge; Lead; Liver; Lymphoma; Lysine; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mission; Modeling; Modification; Mus; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated cancer; Organ; Overweight; Pathway interactions; Plasma; Play; Regulation; Risk; Role; Signal Transduction; Testing; Thermogenesis; Tissues; Triglycerides; Tumor Immunity; United States National Institutes of Health; Work; World Health Organization; acyl group; adiponectin; cell motility; diacylglycerol O-acyltransferase; disability; experimental study; fatty acylation; graduate student; improved; inhibitor/antagonist; lipid metabolism; non-alcoholic fatty liver disease; novel; novel strategies; novel therapeutics; obesity development; obesity treatment; parent grant; student training; treatment strategy

Project Summary Cell metabolism plays a central role in cancer biology including cell proliferation, invasion/metastasis, and drug resistance. In addition to cancer, dysregulated cellular metabolism has been shown to be associated with obesity and the development of many chronic illnesses. According to the World Health Organization >2.1 billion adults are estimated to be overweight or obese globally, and accumulating, consistent, evidence suggests that higher amounts of body fat are associated with increased risks of a number of cancers. Previously, we discovered an essential role of histone deacetylase 11 (HDAC11) in metabolism homeostasis. More recently, our studies revealed a novel enzymatic activity of HDAC11, removing long-chain fatty acyl groups, that is >10,000-fold higher than the presumed deacetylation activity. Further, our recent preliminary studies show: 1) HDAC11 KO promotes the expression of UCP1 and boosts the thermogenic capacity of brown adipose tissue; 2) Lack of HDAC11 elevates the level of plasma adiponectin, a key messenger involved in communicating between adipose tissue and other organs, and suppresses metabolic derangements, leading to type 2 diabetes, obesity, and non- alcoholic fatty liver disease; 3) HDAC11 deficiency not only results in the accumulation of diacylglycerol (DG) and metabolites, but also attenuates the triacylglycerol (TAG) level in the liver, indicating dysfunction of diglyceride acyltransferase 2 (DGAT2). In this diversity supplement application, the Supplement Candidate will rigorously test the hypothesis that the novel defatty-acylation activity of HDAC11 is critical for its impact on HFD-driven metabolic reprogramming. The Candidate will focus on elucidating major HDAC11 KO-driven events in key lipid metabolism tissues by performing the following studies: 1) investigate the role of HDAC11 as a regulator of thermogenesis through the UCP1 pathway in BAT and examine whether HDAC11 altered Cdc42-fatty-acylation plays a crucial role in cAMP/PKA mediated UCP1 expression; 2) examine the effect of HDAC11 on adiponectin function in white adipose tissue and investigate the impact of HDAC11 on adiponectin conserved lysine-modification and multimerization; 3) explore HDAC11 KO-induced suppression of TAG synthesis through affecting DGAT function in liver tissue and investigate the role of BASP1 in DGAT regulation. The proposed experiments in this supplement are distinct from, yet highly relevant to, the proposed work in the parent grant. The supplemental project will contribute to, expands and extends, our understandings of HDAC11 in cancer. Ultimately, it may lead to new approaches for the treatment of obesity-related cancer diseases.

项目摘要 细胞代谢在肿瘤生物学中起着核心作用，包括细胞增殖、侵袭/转移和 抗药性。除了癌症，细胞新陈代谢失调已被证明与 肥胖和许多慢性病的发展。根据世界卫生组织的报告：2.1 据估计，全球有10亿成年人超重或肥胖，而且不断积累的证据 这表明，体内脂肪含量越高，患多种癌症的风险就越高。 在此之前，我们发现了组蛋白脱乙酰酶11(HDAC11)在新陈代谢中的重要作用 动态平衡。最近，我们的研究揭示了HDAC11的一种新的酶活性，即去除长链 脂肪酰基，即&gt；比推定的脱乙酰基活性高10,000倍。此外，我们最近 初步研究表明：1)HDAC11 KO促进UCP1的表达，促进生热 棕色脂肪组织的能力；2)缺乏HDAC11会提高血浆脂联素的水平，脂联素是 参与脂肪组织和其他器官之间通讯的信使，并抑制代谢 基因紊乱，导致2型糖尿病、肥胖症和非酒精性脂肪肝；3)HDAC11 缺乏不仅会导致二酰基甘油(DG)和代谢物的积累，而且还会削弱 肝脏中的三酰甘油(TAG)水平，表明二甘油酰基转移酶2(DGAT2)功能障碍。 在这个多样性补充剂的申请中，补充剂候选人将严格测试以下假设 HDAC11新的脱脂酰化活性对于其影响HFD驱动的代谢重编程是至关重要的。 候选人将专注于阐明关键脂肪代谢组织中HDAC11 KO驱动的主要事件 进行以下研究：1)研究HDAC11作为产热调节因子的作用 BAT中的UCP1途径，并检测HDAC11是否改变了CDC42-脂肪酰化在 CAMP/PKA介导的UCP1表达；2)检测HDAC11对白鼠脂联素功能的影响 脂肪组织，观察HDAC11对脂联素保守的赖氨酸修饰和 3)探讨HDAC11 KO通过影响DGAT抑制Tag合成 并探讨BASP1在DGAT调节中的作用。 本补编中建议的实验与 家长拨款。补充项目将有助于、扩大和延伸我们对 HDAC11在癌症中。最终，它可能会带来治疗肥胖相关癌症的新方法。 疾病。