Abdominal aortic aneurysm (AAA) is a life-threatening disease that so far has no effective treatment other than surgical repair. The high prevalence of AAA, which could be as high as 6% in selected populations, and its catastrophic outcomes give rise to an urgent demand for new diagnostic and drug-based therapeutic methods. The development of AAA is characterized by extensive inflammatory cell infiltration and increased inflammatory cytokines release, emphasizing a role of systemic inflammation in the progression of the disease. Recently, large genome-wide association studies (GWAS) and following biological studies suggested that Krppel-like factor 14 (KLF14), a zinc finger transcription factor, plays a protective role in several inflammatory and metabolic-associated diseases, including atherosclerosis, dyslipidemia and cancer. In order to understand the role of KLF14 during the progression of systemic inflammation and AAA, we established myeloid cell-specific Klf14 knockout mice in the apoE-/- background (Klf14LysM ApoE-/-). After challenging these mice with 42%kCal high fat high cholesterol diet (HFHCD) for 12 weeks, we found significantly increased circulating leukocytes, TNFalpha levels and AAA formation rate, in female mice. Intriguingly, this phenotype also matches population studies, in which female carrying the KLF14 risk allele, associated with lower expression of KLF14, have a more profound phenotype compared to male. This suggests that KLF14 may partially account for the low systemic inflammation as well as AAA prevalence observed in female individuals. Based on previous reports and our preliminary studies, we will test the central hypothesis that KLF14 protects against AAA formation via regulating estrogen receptors (ERs)-mediated anti-inflammatory response in monocytes/macrophages. Firstly, we will determine the role of myeloid-specific KLF14 in AAA formation and systemic inflammation. Secondly, we will define KLF14 as a key transcription factor mediating estrogen-ERs anti-inflammatory mechanisms in macrophages. Overall, we propose a comprehensive characterization of the myeloid influence of KLF14 in the condition of chronic inflammation and AAA. The outcomes from this proposal will provide novel insights into our understanding of a human CVD-relevant gene, KLF14, and its cellular function in the macrophage, and will set the basis for development of new approaches to the treatment of AAA, of high relevance to the AHA mission.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|