The Role of Amino Acid Starvation Response Kinase GCN2 in Abdominal Aortic Aneurysm

氨基酸饥饿反应激酶 GCN2 在腹主动脉瘤中的作用

基本信息

批准号：
10584543
负责人：
Bowen Wang
金额：
$ 40.99万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584543
关键词：
Abdominal Aortic Aneurysm Adopted American Amino Acids Angiotensin II Aorta Arginine Arginine deiminase Automobile Driving Biological Biological Assay Caloric Restriction Cardiovascular Diseases Cell Survival Cells Clinical Clinical Management Co-Immunoprecipitations Cytoprotection Development Diameter Dietary Intervention Disease Elastases Elderly Exhibits Functional disorder Gender Genetic Transcription Health Health Benefit Homeostasis Human In Vitro Inflammatory Intervention Intervention Studies Knock-out Knockout Mice Lead Lesion Leucine Life Mediating Medical Metabolic stress Methionine Modeling Molecular Mus Mutation Newly Diagnosed Operative Surgical Procedures Outcome Paracrine Communication Pathogenesis Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphotransferases Pilot Projects Play Population Post-Translational Protein Processing Prevention Proteins Rattus Recombinant Proteins Regulation Repression Resistance Risk Reduction Rodent Role Rupture Signal Transduction Smooth Muscle Myocytes Specimen Starvation Testing Therapeutic Time Transgenic Organisms Vascular Smooth Muscle abdominal aorta activating transcription factor 3 combat cost dietary dietary restriction effective intervention effective therapy gain of function in vivo innovation knock-down loss of function mortality multi-ethnic mutant novel prevent repaired response screening stress kinase success transcription factor

项目摘要

Project Summary: Abdominal aortic aneurysm (AAA) is a life-threatening disease that afflicts ~1.5 million Americans, particularly in the elderly populations. Despite its high mortality (80-90%) upon rupture, there is a lack of effective drug therapies for clinical management of AAA. Surgical repairs remain the only effective options; however, not only are they considered traumatic and risky, but also not indicated for the majority of newly diagnosed AAA patients. Therefore, there is a pressing unmet need to develop non-surgical strategies to contain AAA progression. Dietary restrictions of amino acids emerge as promising avenues to combat cardiovascular diseases. For the first time, our study demonstrated the potential of dietary methionine or leucine restrictions in inhibiting the development of AAA in a rat model. It is well established that such dietary restrictions trigger the amino acid starvation response, a potent protective mechanism driven by the metabolic stress kinase general control nondepressible 2 (GCN2). Indeed, in our preliminary study, silencing GCN2 in rat abdominal aorta nullified the benefits of methionine restriction against AAA, suggesting a protective role of GCN2 in reinstating aortic homeostasis. Activating GCN2 through methionine restriction protected smooth muscle cells (SMCs) from undergoing degeneration, which is one of the key determinants of AAA pathogenesis; conversely, reduced GCN2 activity was robustly observed in clinical specimens of AAA, and GCN2 silencing effectively compromised the protection against SMC degeneration. Finally, we serendipitously identified GCN2 to be citrullinated by peptidyl arginine deiminase 3 (PADI3) at its 1475 arginine (R1475) residue in the starvation-sensing domain. This post-translational modification (PTM) of GCN2 was increased in AAA and correlated with repressed GCN2 activity. Collectively, these preliminary results lead to our central hypothesis: GCN2 plays a pivotal role in protecting against SMC degeneration and AAA formation, and its activity is negatively modulated by PADI3-mediated citrullination; GCN2-activating strategies offer a new paradigm for effective prevention and intervention of AAA. In Aim 1, we will dissect the role of GCN2 in safeguarding SMC homeostasis as well as its downstream signaling using human and murine SMCs. In Aim 2, we will characterize a new PTM regulation that negatively modulates GCN2 activity and delineate the biological consequences of GCN2 citrullination in SMC. In Aim 3, we will determine the mechanistic and therapeutic implications of GCN2 activation in AAA, utilizing both transgenic (SMC-specific GCN2 knockout mice) and dietary intervention approaches (methionine restriction for treatment of pre-existing AAA lesions). The successful completion of the proposed studies will not only uncover an intrinsic protective mechanism against SMC degeneration and AAA pathogenesis, but also may provide a new paradigm through GCN2-activating dietary restrictions for effective prevention and intervention of AAA.

项目摘要：腹部主动脉瘤（AAA）是一种威胁生命的疾病，遭受约150万美国人，特别是在老年人中。尽管破裂时死亡率很高（80-90％），但仍有一个缺乏用于AAA临床管理的有效药物疗法。手术维修仍然是唯一有效的选项;但是，它们不仅被认为是创伤和冒险的，而且并未指出大多数新诊断为AAA患者。因此，有迫切需要制定非手术策略包含AAA进展。出现氨基酸的饮食限制是应对有前途的途径心血管疾病。我们的研究首次证明了饮食中蛋氨酸或亮氨酸限制在大鼠模型中抑制AAA的发展。众所周知，这种饮食限制触发氨基酸饥饿反应，这是由代谢驱动的有效保护机制应力激酶一般对照非抑制2（GCN2）。实际上，在我们的初步研究中，将大鼠沉默的GCN2沉默腹主动脉无效甲硫氨酸对AAA的好处，这表明保护作用 GCN2恢复主动脉稳态。通过蛋氨酸限制激活GCN2。发生变性的肌肉细胞（SMC），这是AAA的关键决定因素之一发病;相反，在AAA的临床标本中稳健观察到GCN2活性的降低，并且 GCN2沉默有效地损害了SMC变性的保护。最后，我们偶然地鉴定出GCN2在其1475精氨酸（R1475）上被肽基精氨酸脱氨酶3（PADI3）固定饥饿感应域中的残留物。 GCN2的这种翻译后修饰（PTM）在 AAA并与抑制GCN2活性相关。总的来说，这些初步结果导致了我们的中心假设：GCN2在保护SMC变性和AAA形成及其ITS及其及其及其的作用方面起着关键作用 PADI3介导的柠檬酸化对活性进行负调节。 GCN2激活策略提供了新的有效预防和干预AAA的范式。在AIM 1中，我们将剖析GCN2在使用人和鼠SMC来保护SMC稳态及其下游信号。在AIM 2中，我们将表征一种新的PTM调节，该调节对GCN2活性进行负面调节并描述生物学 SMC中GCN2鞭打的后果。在AIM 3中，我们将确定机械和治疗性使用转基因（SMC特异性GCN2基因敲除小鼠）和饮食干预方法（用于治疗预先存在的AAA病变的蛋氨酸限制）。这成功完成拟议的研究不仅会发现一种固有的保护机制 SMC变性和AAA发病机理，但也可以通过GCN2激活提供新的范式有效预防和干预AAA的饮食限制。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dietary therapy in abdominal aortic aneurysm - Insights from clinical and experimental studies.

DOI：
10.3389/fcvm.2022.949262
发表时间：
2022
期刊：
FRONTIERS IN CARDIOVASCULAR MEDICINE
影响因子：
3.6
作者：
Yin, Li;Gregg, Alexander Christopher;Riccio, Alessandra Marie;Hoyt, Nicholas;Islam, Zain Hussain;Ahn, Jungeun;Le, Quang;Patel, Paranjay;Zhang, Mengxue;He, Xinran;McKinney, Matthew;Kent, Eric;Wang, Bowen
通讯作者：
Wang, Bowen

Progress in murine models of ruptured abdominal aortic aneurysm.