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Targeting the Inflammasome to Prevent Thoracic Aortic Aneurysms and Dissections

针对炎症小体预防胸主动脉瘤和夹层

基本信息

批准号：
9247885
负责人：
SCOTT A LEMAIRE
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247885
关键词：
Acute Affect Aneurysm Aortic Aneurysm Aortic Diseases Biomechanics Bone Marrow CASP1 gene Cade Cardiovascular Diseases Caspase Cause of Death Cells Cellular Stress Cessation of life Chest Cleaved cell Contractile Proteins Data Development Disease Disease Progression Dissection Event Extracellular Matrix Failure Functional disorder Glyburide Goals Hospitals Human In Vitro Incidence Infiltration Inflammasome Inflammation Inflammatory Life Medial Mediating Mission Modernization Molecular Multiprotein Complexes Mus Myosin Heavy Chains National Heart, Lung, and Blood Institute Operative Surgical Procedures Patients Peptide Hydrolases Pharmacology Play Prevention Prevention strategy Procedures Proteins Public Health Research Risk Role Series Smooth Muscle Myocytes Stress Structure Testing Therapeutic Agents Thoracic Aortic Aneurysm Thoracic aorta Time Tissues Treatment Efficacy Tropomyosin United States Wild Type Mouse Work base biological adaptation to stress experimental study improved inhibitor/antagonist innovation mortality mouse model outcome forecast parthenolide prevent public health relevance repaired therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Ascending thoracic aortic aneurysms and dissections (ATAAD) are interrelated cardiovascular diseases that carry high mortality.] Current approaches to pharmacologic prevention of ATAAD are ineffective, particularly in patients with sporadic disease. Although there is a critical need to develop new treatment strategies, a major barrier to this goal is a poor understanding of the molecular mechanisms that trigger and then promote aortic degeneration in sporadic ATAAD. Therefore, our long-term goal is to improve the under- standing of the pathobiology of aortic wall degeneration in hope of developing new pharmacological strategies to prevent ATAAD formation and progression. The overall objective of this application is to systematically define the role of the NLRP3 inflammasome cascade, a multiprotein platform involved in amplifying intracellular stress responses, in promoting aortic destruction and the extent to which this cascade represents a therapeutic target against ATAAD. The central hypotheses are: (1) the NLRP3-ASC-caspase-1 cascade promotes aortic degeneration by promoting smooth muscle cell contractile dysfunction and aortic destruction, and (2) treatment with pharmacological inhibitors of this cascade will prevent ATAAD. These central hypotheses will be tested through three specific aims, each of which focuses on specific hypotheses based on our preliminary data. [In the first aim, we will seek to prove our hypothesis that the NLRP3- ASC-caspase-1 inflammasome cascade promotes ascending aortic wall inflammatory cell infiltration, matrix destruction, contractile dysfunction, and biomechanical failure through a series of experiments with a mouse model of sporadic ATAAD. In the second aim, we will seek to prove the hypothesis that the inflammasome cascade directly cleaves and degrades myosin heavy chain and tropomyosin, and thus promotes SMC contractile dysfunction. We will also determine whether intracellular stress activates the inflammasome cascade and confirm the association of intracellular stress and the inflammasome in human ATAAD tissue. In the third aim, we will test the hypothesis that NLRP3 inhibitors (glyburide, parthenolide and MCC950) will prevent ascending aortic destruction and disease progression in our mouse model of sporadic ATAAD.] The proposed research is significant because it will determine how the inflammasome cascade is activated, how this cascade promotes ATAAD development, and the extent to which an inflammasome inhibitor can prevent ATAAD. This research is innovative because it represents a new and substantive departure from the status quo, namely the current pharmacologic approaches to preventing aortic disease progression. The development of a new, effective pharmacological prevention strategy would have an important positive effect on disease prognosis by delaying or obviating invasive procedures in patients presenting with early-stage ascending aortic disease, suppressing disease progression in patients who are poor candidates for surgical treatment, and improving the durability of surgical aortic repairs.