The role of TFEB in aortic aneurysms

TFEB 在主动脉瘤中的作用

基本信息

批准号：
10199015
负责人：
Yanbo Fan
金额：
$ 53.8万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2020-06-20 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199015
关键词：
Abdominal Aortic Aneurysm Amino Acids Aneurysm Animal Model Animals Anti-Inflammatory Agents Aortic Aneurysm ApoE knockout mouse Apolipoprotein E Apoptosis Atherosclerosis Autophagocytosis Bioavailable Biogenesis Blood Vessels Cardiovascular Diseases Cell physiology Clinical Conjugated Linoleic Acids Dependence Detection Diabetes Mellitus Experimental Models Fatty Acids Foundations Functional disorder Histidine Homeostasis Human Impairment In Vitro Inflammation Intervention Knock-out Lead Life Linoleic Acids Lipids MMP2 gene Metabolic Diseases Methodology Modeling Mus Nitrites Nitrogen Dioxide Nuclear Translocation Operative Surgical Procedures Oral Pathologic Patients Pharmacology Phase II Clinical Trials Physiological Plasma Prevention Production Proteins Research Role Rupture Signal Transduction Smooth Muscle Myocytes Solid Stimulus Supplementation Testing Therapeutic Transcriptional Activation Translations Vascular Diseases Vascular Smooth Muscle base clinically relevant human model in vivo inhibitor/antagonist lipidomics metabolomics mortality mouse model nanomolar new therapeutic target nitration nitroalkene novel novel strategies novel therapeutic intervention prevent protective effect transcription factor

项目摘要

ABSTRACT Abdominal Aortic aneurysm (AAA) results in very high mortality upon rupture. To date, besides surgical intervention –with only 10% of patients eligible-, no alternative therapeutic approaches are available. Therefore, it would be of high significance to identify novel strategies to effectively treat or prevent AAA in vivo. Vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular wall integrity and function and VSMC homeostasis is disrupted in AAA. Transcription factor-EB (TFEB) is a “master” regulator of lysosomal biogenesis and autophagy. However, the role of TFEB in VSMC functions and AAA formation remain to be explored. We demonstrated that TFEB inhibits apoptosis, MMP2/9 activity and inflammation in VSMCs. VSMC specific TFEB knockout (KO) significantly aggravates vascular wall matrix degradation in a mouse AAA model. Nitroalkene derivatives of fatty acids such as oleic (OA-NO2) and linoleic acid (LNO2) have profound protective effects against cardiovascular and metabolic diseases. Conjugated linoleic acid (CLA) was identified as the preferential and major nitrated endogenous fatty acid and is readily bioavailable in humans and experimental models upon oral delivery of CLA and inorganic nitrite (NO2), making it an attractive intervention for CVD. We found that nitro-CLA protects against AAA formation in the Ang II-induced AAA mouse model and inhibits VSMC inflammation and apoptosis in a TFEB-dependent manner. It also promotes TFEB nuclear translocation in vitro in an H148-dependent fashion suggesting that TFEB is a direct target of nitro-CLA. Based on these evidences, we will test the central hypothesis that activation of TFEB by enhancing the endogenous production of nitro-CLA protects against AAA formation through inhibition of VSMC dysfunction. By taking advantage of our unique animal models generated specifically for these studies and the combined expertise of the assembled team, we propose 3 aims. Aim 1: Characterize the protective role of VSMC TFEB in AAA formation. We will test our working sub-hypothesis that VSMC TFEB protects against AAA formation through inhibition of VSMC dysfunction. Aim 2: Determine that activation of TFEB by nitro-CLA inhibits VSMC dysfunction in vitro. The working sub-hypothesis is that nitro-CLA prevents VSMC dysfunction in a TFEB-dependent manner. Aim 3: Define TFEB as a novel therapeutic target for nitro-CLA inhibition of AAA formation in vivo. The working sub- hypothesis is that endogenous production of nitro-CLA protects against AAA formation through activation of VSMC TFEB. In summary, we will characterize the protective role of TFEB in AAA formation and establish nitro-CLA as a novel therapeutic strategy against AAA by targeting VSMC TFEB. This mechanistic research will set a solid foundation for rapid translation into clinical utilization of nitro-CLA and may lead to a breakthrough for treatment or/and prevention of AAA.

抽象的迄今为止，除了手术治疗外，腹主动脉瘤（AAA）破裂后的死亡率非常高。干预——只有 10% 的患者符合条件——没有替代治疗方法可用。因此，寻找有效治疗或预防体内 AAA 的新策略具有重要意义。血管平滑肌细胞 (VSMC) 对于维持血管壁完整性和功能至关重要 AAA 中 VSMC 稳态被破坏，转录因子-EB (TFEB) 是溶酶体的“主要”调节因子。然而，TFEB 在 VSMC 功能和 AAA 形成中的作用仍有待研究。我们证明 TFEB 抑制 VSMC 中的细胞凋亡、MMP2/9 活性和炎症。特异性 TFEB 敲除 (KO) 显着加剧小鼠 AAA 模型中的血管壁基质降解。脂肪酸的硝基烯烃衍生物，例如油酸（OA-NO2）和亚油酸（LNO2）具有深远的保护作用共轭亚油酸（CLA）被确定为对心血管和代谢疾病的作用。优先且主要的硝化内源性脂肪酸，并且易于在人体和实验中生物利用我们建立了口服 CLA 和无机亚硝酸盐 (NO2) 的模型，使其成为一种有吸引力的 CVD 干预措施。发现硝基-CLA 可防止 Ang II 诱导的 AAA 小鼠模型中的 AAA 形成并抑制 VSMC 炎症和细胞凋亡以 TFEB 依赖性方式进行。它还促进 TFEB 核转位。体外以 H148 依赖的方式表明 TFEB 是硝基-CLA 的直接靶标。证据，我们将检验中心假设，即通过增强内源性生产来激活 TFEB 硝基-CLA 通过抑制 VSMC 功能障碍来防止 AAA 形成。我们专门为这些研究和综合专业知识而生成的独特动物模型组建团队后，我们提出了 3 个目标：目标 1：表征 VSMC TFEB 在 AAA 形成中的保护作用。我们将测试我们的工作子假设，即 VSMC TFEB 通过抑制目标 2：确定硝基 CLA 激活 TFEB 可抑制体外 VSMC 功能障碍。工作子假设是硝基-CLA 以 TFEB 依赖性方式预防 VSMC 功能障碍。图 3：将 TFEB 定义为硝基 CLA 抑制体内 AAA 形成的新型治疗靶点。假设硝基-CLA 的内源产生通过激活 AAA 来防止 AAA 的形成。总之，我们将描述 TFEB 在 AAA 形成中的保护作用并建立硝基-CLA 作为一种针对 AAA 的新型治疗策略，通过针对 VSMC TFEB 这一机制研究。将为硝基-CLA的快速转化为临床应用奠定坚实的基础，并可能导致治疗或/和预防 AAA 的突破。