Hypoxia, HIF-1, and the progression of nonalcoholic fatty liver disease in obstructive sleep apnea

阻塞性睡眠呼吸暂停中的缺氧、HIF-1 和非酒精性脂肪肝的进展

基本信息

批准号：
10436877
负责人：
Omar Mesarwi
金额：
$ 17.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436877
关键词：
Animals Antisense Oligonucleotides Cessation of life Chronic Cirrhosis Communication Data Data Analyses Development Disease Disease Progression Disease model Enzymes Event Experimental Designs Family Fatty Liver Fibrosis Fostering Genetic Transcription Glucose Goals Hepatic Hepatic Stellate Cell Hepatocyte Histologic Hypoxia Hypoxia Inducible Factor Impairment In Vitro Inflammation Insulin Resistance Knock-out Knowledge Kupffer Cells Laboratories Laboratory Procedures Lead Link Liver Liver Failure Liver Fibrosis Liver diseases Malignant neoplasm of liver Mediating Mediator of activation protein Mentors Metabolic Metabolic dysfunction Metabolic syndrome Methods Modeling Mus Obesity Obstructive Sleep Apnea Oxygen Pathogenicity Pathway interactions Patients Pharmacology Phenotype Physicians Play Proteins RNA Interference Recurrence Research Rodent Role Scientist Severities Sleep Techniques Testing Therapeutic Training Training Programs Transplantation Whole-Genome Shotgun Sequencing Work adverse outcome career cell type design diet-induced obesity disease phenotype fatty acid metabolism glucose metabolism glucose output human subject hypoxia inducible factor 1 in vivo in vivo Model insight knock-down laboratory experience lipid metabolism liver hypoxia liver injury liver metabolism mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis prevent response sensor skills therapeutic target tool transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT The objectives of this K08 proposal are: a) To foster the development of critical scientific and professional skills which will allow the candidate, Dr. Omar Mesarwi, to progress toward his goal of becoming an independent physician-scientist, examining the metabolic consequences of obstructive sleep apnea (OSA); and b) To determine how intermittent hypoxia (IH) in OSA may impact the development and progression of nonalcoholic fatty liver disease (NAFLD). Dr. Mesarwi and his mentors at UC San Diego have designed a comprehensive training plan that will afford Dr. Mesarwi new knowledge and research skills in the pathobiology of metabolic dysfunction in OSA. This will be accomplished through extensive laboratory experience and coursework at UC San Diego, which will provide Dr. Mesarwi additional expertise in experimental design, laboratory procedures, data analysis, and scientific communication. OSA is a common condition which is characterized by recurrent upper airway narrowing during sleep, leading to chronic IH. OSA is associated with a more severe NAFLD phenotype, driven by IH. NAFLD is an extremely prevalent condition in which hepatic steatosis and dysregulated glucose metabolism may ultimately lead to cirrhosis, need for transplant, and liver-related death. The mechanisms which link OSA and NAFLD are relatively unknown. Previous animal work has demonstrated that IH exacerbates hepatic steatosis and fibrosis in mice with diet-induced obesity, mirroring findings in human subjects. Hepatic steatosis in experimental NAFLD reduces liver oxygen tension; it is further reduced with superimposed IH. Hepatic steatosis also increases hypoxia inducible factor-1 (HIF-1), a regulator of the cellular response to hypoxia. We have shown that hepatocyte HIF-1 mediates the expression of several key enzymes of fatty acid metabolism in the liver, and the progression of liver fibrosis in experimental NAFLD. Therefore, we hypothesize that IH in OSA may worsen the NAFLD phenotype through HIF-1 activation and its downstream effects. We will test this hypothesis in three Specific Aims: 1) Determine the role of HIF-1 as a mediator of IH- induced hepatic steatosis and dysregulated hepatic glucose metabolism; 2) Determine the role of HIF-1 on IH- induced hepatic fibrosis in mice with experimental NAFLD, and the effect of antisense oligonucleotides targeting HIF-1α in reversing liver fibrosis; and 3) Determine the role of HIF-1 and IH in mediating liver fibrosis in other hepatic cell types. Tools available to us include cell type-specific HIF-1α knockout, which will help localize HIF-1 effects. Major methods for this proposal include co-modeling OSA and NAFLD in rodents, antisense knockdown of hepatic HIF-1α, RNA interference, and whole genome shotgun sequencing (RNA- Seq). Successful implementation of these Specific Aims will provide a rigorous training program for Dr. Mesarwi, laying the groundwork for R01 submission, and will allow us to answer a fundamentally important question about the role of hypoxia and HIF-1 in patients with OSA and NAFLD, and possibly to credential HIF-1 and/or its downstream mediators as therapeutic targets in preventing metabolic derangement in OSA.

项目概要/摘要 K08 提案的目标是： a) 促进关键科学和专业技能的发展这将使候选人 Omar Mesarwi 博士能够朝着成为独立人士的目标迈进医生兼科学家，检查阻塞性睡眠呼吸暂停 (OSA) 的代谢后果；以及 b) 确定 OSA 中的间歇性缺氧 (IH) 如何影响非酒精性睡眠障碍的发生和进展 Mesarwi 博士和他在加州大学圣地亚哥分校的导师设计了一个全面的脂肪肝疾病 (NAFLD) 治疗方案。培训计划将为 Mesarwi 博士提供代谢病理学方面的新知识和研究技能 OSA 功能障碍将通过 UC 的丰富实验室经验和课程来实现。圣地亚哥，这将为 Mesarwi 博士提供实验设计、实验室程序、 OSA 是一种常见病症，其特点是反复发作。睡眠期间上呼吸道变窄，导致慢性阻塞性睡眠呼吸暂停 (OSA) 与更严重的 NAFLD 相关。由 IH 驱动的表型是一种极其普遍的疾病，其中肝脂肪变性和葡萄糖代谢失调可能最终导致肝硬化、移植需要以及与肝脏相关的死亡。 OSA 和 NAFLD 之间的联系机制目前尚不清楚。 IH 会加重饮食引起的肥胖小鼠的肝脏脂肪变性和纤维化，这与人类的研究结果相似实验性 NAFLD 中的肝脏脂肪变性会降低肝脏氧张力；叠加的 IH 还会导致细胞缺氧诱导因子 1 (HIF-1) 的增加。我们已经证明肝细胞 HIF-1 介导几种关键酶的表达。肝脏中脂肪酸代谢的变化以及实验性 NAFLD 中肝纤维化的进展。促进 OSA 中的 IH 可能通过 HIF-1 激活及其下游使 NAFLD 表型恶化我们将在三个具体目标中检验这一假设：1) 确定 HIF-1 作为 IH- 介导物的作用。诱导肝脏脂肪变性和肝脏葡萄糖代谢失调 2) 确定 HIF-1 对 IH- 的作用；诱导实验性 NAFLD 小鼠肝纤维化以及反义寡核苷酸的作用靶向 HIF-1α 逆转肝纤维化；3) 确定 HIF-1 和 IH 在介导肝纤维化中的作用我们可用的工具包括细胞类型特异性 HIF-1α 敲除，这将有所帮助。该提案的主要方法包括对啮齿动物中的 OSA 和 NAFLD 进行联合建模，肝脏 HIF-1α 的反义敲低、RNA 干扰和全基因组鸟枪测序 (RNA- Seq）的成功实施将为博士提供严格的培训计划。 Mesarwi，为 R01 提交奠定了基础，将使我们能够回答一个根本性的重要问题关于缺氧和 HIF-1 在 OSA 和 NAFLD 患者中的作用的问题，以及可能的凭证 HIF-1 和/或其下游介质作为预防 OSA 代谢紊乱的治疗靶点。