Role of Inflammation in the Pathobiology of Abdominal Aortic Aneurysm

炎症在腹主动脉瘤病理学中的作用

• 批准号: 8760303
• 负责人: Kathleen Raman
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760303
• 关键词: Abdominal Aortic Aneurysm; Acute; Advanced Glycosylation End Products; Affect; Aorta; Apoptosis; Apoptotic; Atherosclerosis; Biology; Blood Vessels; Bone Marrow; Caliber; Cell Culture Techniques; Cells; Chronic; Cytoplasmic Tail; Data; Development; Dominant Negative Receptor; Elastases; Elastic Fiber; Elastin; Environmental Risk Factor; Family; Functional disorder; Gelatinase B; Genetic; HMGB1 Protein; Health; Human; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lead; Leukocyte L1 Antigen Complex; Leukocytes; Life; Ligand Binding; Ligands; Link; Macrophage Activation; Matrix Metalloproteinases; Measures; Medial; Mediating; Mediator of activation protein; Molecular; Mus; Pathogenesis; Pattern; Peptide Hydrolases; Perfusion; Phenotype; Population; Prevention strategy; Primary Cell Cultures; Protein Family; RNA; Receptor Activation; Receptor Inhibition; Research Project Grants; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Staining method; Stains; Stimulus; Technology; Testing; Time; Tissue Inhibitor of Metalloproteinases; Tissues; Transgenic Mice; Vascular Diseases; Veterans; Wild Type Mouse; cell behavior; clinically relevant; cytokine; in vitro Model; in vivo; indexing; innovation; macrophage; member; mouse model; novel diagnostics; novel therapeutics; promoter; receptor; reconstitution; tool

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) are a common and potentially life-threatening vascular condition prevalent among US veterans. Aortic wall inflammation results in two fundamental structural changes which underlie AAA; elastin degradation and loss of smooth muscle cells (SMC) within the aortic media. Aneurysmal degeneration is related to increased elaboration and activity of elastin-specific proteinases, particularly matrix metalloproteinases (MMPs). While macrophages and SMC are key cellular mediators in the pathogenesis of AAAs; the upstream stimulus which triggers the inflammatory cascade responsible for matrix changes remains unknown. Activation of the receptor for advanced glycation end products (RAGE) leads to both an acute inflammatory response and perpetuation of a chronic, sustained inflammatory state leading to tissue damage. Additionally, along with endogenous tissue inhibitors of metalloproteinases (TIMPs), RAGE upregulates the expression and activity of MMPs including MMP-9, a protease expressed by macrophages that is critical to AAA formation. SMC apoptosis has been linked to the interaction of RAGE with diaphanous 1 (mDia-1). RAGE blockade may be effected using soluble RAGE (sRAGE), a ligand-binding decoy of RAGE, as well as RAGE null mice. Transgenic mice in which SMCs express dominant negative (DN) RAGE driven by the SM22¿ promoter allow assessment of cell-specific contributions of RAGE activation. We hypothesize that RAGE alters macrophage polarization and SMC apoptosis, leading to matrix degeneration fundamental to AAA development. Thus, the specific aims of this proposal are: Aim #1: Determine if RAGE-mediated signaling alters macrophage activation and polarization underlying the proinflammatory pathophysiology of AAA. We hypothesize that RAGE mediates the polarization of macrophages from an M2 (reparative) to an M2 (inflammatory) phenotype that transmits a damage signal and contributes to AAA. We will delineate the M1 and M2 subtypes in the aortic tissues of RAGE null, sRAGE-treated, and untreated mice following elastase perfusion. We will confirm our findings with in vitro studies using primary bone marrow derived macrophages stimulated with RAGE ligands to determine the effects of RAGE on MMP and TIMP activity and macrophage polarization. We will reconstitute RAGE null mice with RAGE-sufficient bone marrow to determine whether the presence of RAGE on bone marrow derived leukocytes is sufficient to polarize macrophages into an M1 subtype in the aorta of elastase-perfused mice. Aim #2: Characterize if RAGE-mediated SMC apoptosis within the aortic wall leads to the pathogenesis of AAA. We hypothesize that RAGE, through its interaction with mDia-1, mediates SMC apoptosis and proliferation within the aortic wall. We will utilize SMC DN RAGE mice to assess SMC-specific contributions of RAGE activation in elastase-induced AAA. Using Ki67 and TUNEL staining, we will quantify proliferative and apoptotic indices in SMCs of elastase-perfused aorta of wild-type, RAGE null, and sRAGE- treated wild-type mice. In vitro, we will stimulate primary aortic SMC with RAGE ligands and measure effects of RAGE on SMC proliferative and apoptotic indices. We will determine if mDia-1 is necessary for RAGE's effects using inhibitory RNA technology. This proposal is innovative in that we will use in vivo and in vitro models to understand how RAGE-mediated alterations in macrophage polarization and SMC apoptosis result in AAA development. The studies described in this proposal may eventually lead to novel diagnostic and therapeutic strategies for prevention and treatment. The clinical relevance of this proposal is underscored by the increasing incidence of AAAs among the VA population and the limited treatment options that are currently available.

描述（由申请人提供）：