Smooth muscle cell PRDM16 and aortic aneurysm

平滑肌细胞PRDM16与主动脉瘤

• 批准号: 10456021
• 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
• 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/10456021
• 关键词: Abdominal Aortic Aneurysm; Address; Adipose tissue; Adult; Affect; Aneurysm; Animal Model; Aorta; Aortic Aneurysm; Apolipoprotein E; Apoptosis; Binding; 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; nitrated conjugated linoleic acid; nitration; novel; oral supplementation; oxidation; prevent; protective effect; repaired; transcriptomics; vascular smooth muscle cell proliferation

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 β (TGF-β) and A disintegrin A metalloprotease 12 (ADAM12) in VSMC. TGF-β 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..

项目摘要/摘要 主动脉瘤（AA）是一种无症状疾病，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主动脉瘤的唯一治疗选择。不 药物已被批准用于治疗这种毁灭性疾病。虽然手术干预是有效的 但是，防止破裂，它通常与手术并发症有关，导致严重发病 甚至死亡率。那，AA仍然是一种威胁生命的疾病。不幸的是，机制 动脉瘤开发在很大程度上未知，这限制了治疗药物的开发 动脉瘤和解剖。这凸显了迫切需要更好地理解动脉瘤的形成和 进展。包含16（PRDM16）的PR结构域是转录调节剂，在 包括造血，心肌细胞和平滑肌细胞在内的细胞的测定和开发。 PRDM16种系或血管平滑肌细胞（VSMC）选择性敲除小鼠的胚胎致命， 强调了PRDM16在VSMC的发展过程中的重要性。尚不知道是否 VSMC中的PRDM16将影响腹主动脉瘤（AAA）的发展。我们的初步数据 表明AAA患者主动脉的PRDM16显着降低，并且PRDM16 SNP与 与人类AA破裂。他莫昔芬诱导的VSMC选择性PRDM16小鼠的敲除导致显着 AAA病变中弹性蛋白降解的增加。这些数据表明，PRDM16功能的丧失会促进 AAA组。我们进一步发现，PRDM16负调节转化生长的表达 VSMC中的因子β（TGF-β）和A脱发蛋白A金属蛋白酶12（ADAM12）。 TGF-β诱导ADAM12 与细胞凋亡呈正相关的表达。另外，共轭亚油酸（CLA）是 Omega-3衍生物是硝化的首选内源性底物。有趣的是，口服交付 CLA和无机亚硝酸盐（NO2）产生内源性硝化CLA（NO2-CLA）。 NO2-CLA是下一代 硝基脂肪酸和人类中最丰富的内源性产生。我们的初步数据文档 NO2-CLA稳定PRDM16蛋白，并防止体内AAA形成和进展。另外，no2- CLA以PRDM16依赖性方式抑制VSMC的凋亡和感染，这是AAA的两个标志。 因此，我们将具体并系统地解决了“内生生产”的中心假设 NO2-CLA可预防VSMC中通过PRDM16的AAA形成和进展。” 该建议是：1）确定VSMC中的PRDM16可防止AAA的形成和进展； 2） 确定PRDM16通过抑制TGF-β/ADAM12信号传导来预防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。 这项工作将将PRDM16定义为AAA的新型治疗靶点，并建立开发一个基础 可行的新口服治疗方法..