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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要细胞代谢在癌症生物学中发挥着核心作用，包括细胞增殖、侵袭/转移和耐药性。除了癌症之外，细胞代谢失调已被证明与以下因素有关：肥胖和许多慢性疾病的发展。根据世界卫生组织 >2.1 据估计，全球有 10 亿成年人超重或肥胖，并且不断积累一致的证据研究表明，体内脂肪含量较高与多种癌症的风险增加有关。之前，我们发现组蛋白脱乙酰酶 11 (HDAC11) 在代谢中的重要作用体内平衡。最近，我们的研究揭示了 HDAC11 的一种新型酶活性，可去除长链脂肪酰基，即比假定的脱乙酰活性高 >10,000 倍。此外，我们最近初步研究表明：1）HDAC11 KO促进UCP1的表达并增强生热棕色脂肪组织的容量； 2) 缺乏 HDAC11 会提高血浆脂联素水平，脂联素是关键参与脂肪组织和其他器官之间沟通的信使，并抑制代谢精神错乱，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甘油（DG）和代谢物的积累，还会减弱肝脏中的三酰甘油 (TAG) 水平，表明甘油二酯酰基转移酶 2 (DGAT2) 功能障碍。在此多样性补充申请中，补充候选人将严格测试以下假设： HDAC11 的新型脱脂酰化活性对于 HFD 驱动的代谢重编程的影响至关重要。候选人将重点阐明关键脂质代谢组织中 HDAC11 KO 驱动的主要事件进行以下研究：1）通过以下方式研究 HDAC11 作为产热调节剂的作用 BAT 中的 UCP1 通路，并检查 HDAC11 改变的 Cdc42 脂肪酰化是否在 cAMP/PKA 介导的 UCP1 表达； 2) 检查HDAC11对白色脂联素功能的影响脂肪组织并研究 HDAC11 对脂联素保守赖氨酸修饰和多聚化； 3) 探索HDAC11 KO通过影响DGAT诱导的TAG合成抑制肝组织中的功能并研究 BASP1 在 DGAT 调节中的作用。本补充中提出的实验与中提出的工作不同，但高度相关。家长补助金。补充项目将有助于、扩展和延伸我们对 HDAC11 在癌症中的作用。最终，它可能会带来治疗肥胖相关癌症的新方法疾病。