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 细胞代谢在癌症生物学中起着核心作用，包括细胞增殖、侵袭/转移和转移。 耐药性除了癌症，细胞代谢失调已被证明与癌症有关。 肥胖和许多慢性疾病的发展。世界卫生组织（WHO）2.1 据估计，全球有10亿成年人超重或肥胖， 研究表明，体内脂肪含量较高与多种癌症的风险增加有关。 以前，我们发现组蛋白去乙酰化酶11（HDAC 11）在代谢中的重要作用 体内平衡最近，我们的研究揭示了HDAC 11的一种新的酶活性， 脂肪酰基，即比假定的脱乙酰化活性高> 10，000倍。此外，我们最近 初步研究表明：1）HDAC 11 KO可促进UCP 1的表达，增强产热细胞的增殖， 2）HDAC 11的缺乏提高了血浆脂联素的水平，这是一个关键因素。 信使参与脂肪组织和其他器官之间的沟通，并抑制代谢 紊乱，导致2型糖尿病、肥胖和非酒精性脂肪肝; 3）HDAC 11 缺乏不仅导致二酰基甘油（DG）和代谢产物的积累，而且还减弱了 肝脏中的甘油三酯（TAG）水平，指示甘油二酯酰基转移酶2（DGAT 2）的功能障碍。 在这个多样性补充申请中，补充候选人将严格测试假设， HDAC 11的新的去脂肪酰化活性对于其对HFD驱动的代谢重编程的影响是关键的。 候选人将通过以下方式重点阐明关键脂质代谢组织中的主要HDAC 11 KO驱动事件： 进行以下研究：1）研究HDAC 11作为产热调节剂的作用， BAT中UCP 1通路，并检查HDAC 11是否改变Cdc 42-脂肪酰化在 cAMP/PKA介导的UCP 1表达; 2）检测HDAC 11对白色小鼠脂联素功能的影响。 研究HDAC 11对脂联素保守赖氨酸修饰的影响， 3）探索HDAC 11 KO通过影响DGAT诱导的TAG合成抑制 在肝组织中的功能，并研究BASP 1在DGAT调节中的作用。 在本补充建议的实验是不同的，但高度相关，拟议的工作， 家长补助金补充项目将有助于，扩大和扩展，我们的理解， HDAC 11与癌症最终，它可能会导致治疗肥胖相关癌症的新方法 疾病