Smooth muscle cell PRDM16 and aortic aneurysm

平滑肌细胞PRDM16与主动脉瘤

基本信息

批准号：
10117682
负责人：
Lin Chang
金额：
$ 67.87万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117682
关键词：
Abdominal Aortic Aneurysm Address Adipose tissue Adult Affect Aneurysm Animal Model Aorta Aortic Aneurysm Apolipoprotein E Apoptosis Binding Bioavailable Blood Vessels Cardiac Myocytes Cardiovascular Diseases Cell Proliferation Cell physiology Cells Clinical Conjugated Linoleic Acids Crossbreeding Data Dependence Development Developmental Process Disease Disintegrins Dissection Drug Targeting Elastin Embryo Fatty Acids Foundations Functional disorder GTP-Binding Protein alpha Subunits, Gs Gene Expression Generations Genes Genetic Transcription Heart Hematopoiesis Hematopoietic Homeostasis Human Impairment Inflammation Knock-in Mouse Knock-out Knockout Mice Lead Lesion Life Linoleic Acids Lysine Mediating Medical Messenger RNA Metalloproteases Modeling Morbidity - disease rate Mus Nitrites Nitrogen Dioxide Oleic Acids Omega-3 Fatty Acids Operative Surgical Procedures Oral Oral Administration Oxidants Pathologic Patients Pharmaceutical Preparations Pharmacology Play Positioning Attribute Prevalence Prevention Procedures Production Proteins Public Health Regulation Research Resistance Role Rupture Ruptured Aortic Aneurysms Scheme Signal Pathway Signal Transduction Smooth Muscle Myocytes Solid Stimulus Stomach Surgical complication Tamoxifen Therapeutic Transforming Growth Factor beta Transforming Growth Factors Transgenic Mice Vascular Smooth Muscle Work abdominal aorta cytokine drug development genome wide association study in vivo loss of function migration mortality new therapeutic target next generation nitration novel oral supplementation oxidation prevent protective effect repaired transcriptomics vascular smooth muscle cell proliferation

项目摘要

Project Summary/Abstract Aortic aneurysm (AA) is an asymptomatic disease with high mortality rate (65% to 85%) if rupture occurs. Repair through open or endovascular surgery is currently the only therapeutic option for aortic aneurysm. No drug has been approved for the treatment of this devastating disease. While surgical intervention is effective in preventing rupture, it is however often associated with surgical complications that result in severe morbidity and even mortality. Thus, AA is still a life-threatening disease. Unfortunately, the mechanisms underlying aneurysm development are largely unknown, which is limiting development of medications for treatment of aneurysms and dissections. This highlights an urgent need for better understanding of aneurysm formation and progression. PR domain containing 16 (PRDM16) is a transcriptional regulator and plays crucial roles in the determination and development of cells including hematopoietic, cardiomyocytes and smooth muscle cells. Prdm16 germline or vascular smooth muscle cell (VSMC) selective knockouts are embryonic lethal in mice, highlighting the importance of PRDM16 in the developmental processes of VSMC. It is not yet known whether PRDM16 in VSMC will affect the development of abdominal aortic aneurysm (AAA). Our preliminary data indicate that PRDM16 is significantly reduced in aorta of AAA patients and the PRDM16 SNP is associated with human AA rupture. Tamoxifen-induced VSMC-selective Prdm16 knockout in mice results in a significant increase in elastin degradation in AAA lesions. These data suggest that loss of PRDM16 function promotes AAA formation. We further uncovered that PRDM16 negatively regulates expression of transforming growth factor  (TGF-β) and A disintegrin A metalloprotease 12 (ADAM12) in VSMC. TGF-induces ADAM12 expression which is positively correlated with cell apoptosis. Additionally, conjugated linoleic acid (cLA) is an omega-3 derivative that serves as the preferential endogenous substrate of nitration. Interestingly, oral delivery of cLA and inorganic nitrite (NO2) yields endogenous nitrated cLA (NO2-cLA). NO2-cLA is a next generation nitro-fatty acid and the most abundant endogenously produced in humans. Our preliminary data document that NO2-cLA stabilizes PRDM16 protein and protects against AAA formation and progression in vivo. Also, NO2- cLA inhibits VSMC apoptosis and inflammation, two hallmarks of AAA, in a PRDM16-dependent manner. Therefore, we will specifically and systematically address the central hypothesis that “endogenous production of NO2-cLA protects against AAA formation and progression through PRDM16 in VSMC”. The specific aims of this proposal are to: 1) determine that PRDM16 in VSMC prevents AAA formation and progression; 2) determine that PRDM16 protects against VSMC dysfunction through inhibition of TGF-β/ADAM12 signaling; and 3) determine that endogenous production of NO2-cLA protects against AAA through PRDM16 in VSMC. This work will define PRDM16 as a novel therapeutic target for AAA and establish the basis to develop a feasible new oral therapeutic approach..

项目概要/摘要主动脉瘤（AA）是一种无症状的疾病，如果发生破裂，死亡率很高（65%至85%）。通过开放或血管内手术修复是目前主动脉瘤的唯一治疗选择。药物已被批准用于治疗这种毁灭性的疾病，而手术干预对于治疗这种疾病是有效的。防止破裂，但通常与导致严重发病率的手术并发症相关不幸的是，AA 仍然是一种危及生命的疾病。动脉瘤的发展在很大程度上是未知的，这限制了治疗动脉瘤的药物的开发这凸显了迫切需要更好地了解动脉瘤的形成和夹层。 PR 结构域 16 (PRDM16) 是一种转录调节因子，在该过程中发挥着至关重要的作用。细胞的测定和发育，包括造血细胞、心肌细胞和平滑肌细胞。 Prdm16 种系或血管平滑肌细胞 (VSMC) 选择性敲除对小鼠胚胎是致命的，强调 PRDM16 在 VSMC 发育过程中的重要性尚不清楚。 VSMC中的PRDM16会影响腹主动脉瘤（AAA）的发展。表明 PRDM16 在 AAA 患者的主动脉中显着减少，并且 PRDM16 SNP 相关他莫昔芬诱导的小鼠 VSMC 选择性敲除 Prdm16 导致显着的人类 AA 破裂。这些数据表明 PRDM16 功能的丧失会促进 AAA 病变中弹性蛋白降解的增加。我们进一步发现 PRDM16 负向调节转化生长的表达。 VSMC 中的因子 β (TGF-β) 和解整合素 A 金属蛋白酶 12 (ADAM12) 诱导 ADAM12。此外，共轭亚油酸（cLA）的表达与细胞凋亡呈正相关。 omega-3 衍生物，作为硝化的优先内源底物。 cLA 和无机亚硝酸盐 (NO2) 产生内源性硝化 cLA (NO2-cLA) 是下一代。我们的初步数据证明，硝基脂肪酸是人类内源产生的最丰富的脂肪酸。 NO2-cLA 可稳定 PRDM16 蛋白并防止体内 AAA 的形成和进展。 cLA 以 PRDM16 依赖性方式抑制 VSMC 凋亡和炎症（AAA 的两个标志）。因此，我们将具体系统地阐述“内生生产”这一中心假设。 NO2-cLA 通过 VSMC 中的 PRDM16 防止 AAA 形成和进展”。该提案旨在：1) 确定 VSMC 中的 PRDM16 可以阻止 AAA 的形成和进展；2) 确定 PRDM16 通过抑制 TGF-β/ADAM12 信号传导来防止 VSMC 功能障碍； 3) 确定 NO2-cLA 的内源性产生通过 VSMC 中的 PRDM16 预防 AAA。这项工作将把 PRDM16 定义为 AAA 的新治疗靶点，并为开发新的治疗靶点奠定基础。可行的新口腔治疗方法。