MicroRNA Regulation of Endothelial Progenitor Senescence in HIV Infection

HIV 感染中内皮祖细胞衰老的 MicroRNA 调控

• 批准号: 8847025
• 负责人: CHUNMING DONG
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847025
• 关键词: Acquired Immunodeficiency Syndrome; Age; Aging; Animal Model; Apoptosis; Arterial Injury; Atherosclerosis; Biology; Blood Vessels; Bone Marrow; Bone Marrow Cells; CDKN2A gene; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chronic; Clinical; Development; Dimensions; Disease; Event; Gene Targeting; Genes; Genetic study; Genomics; HIV-1; Health; Homeostasis; Individual; Infection; Inflammatory; Injury; Investigation; Knowledge; Laboratory culture; Link; Literature; Longevity; Mediating; Messenger RNA; MicroRNAs; Modification; Molecular; Morbidity - disease rate; Pathogenesis; Pathway interactions; Play; Process; Recording of previous events; Regulation; Research; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Smoking; Stem cells; Techniques; Testing; Vascular Endothelial Growth Factors; antiretroviral therapy; atherogenesis; base; cardiovascular disorder risk; design; differential expression; exhaustion; functional disability; immune activation; mRNA Expression; mortality; normal aging; novel strategies; novel therapeutics; p19ARF; premature; progenitor; public health relevance; repaired; response to injury; screening; self-renewal; senescence; stem; transcriptome sequencing

DESCRIPTION (provided by applicant): Human immunodeficiency virus-1 (HIV) infection accelerates cellular and organismal aging and substantially increases the risk of atherosclerosis. Endothelial progenitor cells (EPC) are actively involved in vascular homeostasis and arterial repair and can predict cardiovascular events. Senescent EPC have impaired repair capacity, which is associated with atherosclerosis development. The impact of HIV infection on EPC and the underlying mechanisms remain to be elucidated. MicroRNAs (miRNA) regulate the senescence of somatic stem cells. We have identified miR-10A*, miR-21, miR-146a, miR-29c and miR-126, as well as, their target genes, to be differentially expressed in young and old EPC/lineage negative bone marrow cells (lin- BMC) using genomic screening. Furthermore, we have demonstrated that these miRNA/target genes segregate into three miRNA signaling axes that control different basic processes of EPC/lin- BMC. Specifically, miR- 10A*/miR-21 —↓hmga2 —↑p16Ink4a/p19Arf mainly regulates cell self-renewal; miR-146a —↓Plk2 pathway chiefly controls cell apoptosis; and miR-29c —↓klf2a —↓miR-126 —↑spred-1 —↓VEGF signaling predominantly governs differentiation, respectively. In addition, we have shown that modifying these three pathways can dramatically impact the senescence and the angiogenic and vascular repair capacity of EPC. The primary objective of the current proposal is to understand the impact of HIV infection on the circulating levels and functionality of EPC and the underlying mechanisms. Our central hypotheses are that HIV infection is associated with EPC senescence, which contributes to accelerated atherogenesis, and that the specific miRNA regulatory networks mediate this process. We will test these proof-of-principle hypotheses by examining the EPC levels in well- characterized clinical samples using multiple standardized approaches/techniques and testing their functionality using established cell culture procedures. We will further determine the role of candidate miRNA regulatory networks in mediating the effects of HIV on EPC functions. Results from these studies will offer understanding of EPC changes and the underlying molecular mechanisms in the pathogenesis of HIV- associated accelerated atherosclerosis, and may open an avenue for facilitating the design of novel therapeutic strategies for HIV-associated cardiovascular disease.

描述（由申请人提供）：人类免疫缺陷病毒-1 (HIV) 感染会加速细胞和生物衰老，并显着增加动脉粥样硬化的风险。内皮祖细胞 (EPC) 积极参与血管稳态和动脉修复，并可以预测心血管事件。衰老的EPC修复能力受损，这与动脉粥样硬化的发展有关。HIV感染对EPC的影响及其潜在机制仍有待阐明。 MicroRNA (miRNA) 调节成体干细胞的衰老，我们已经鉴定出 miR-10A*、miR-21、miR-146a、miR-29c 和 miR-126 及其靶基因在年轻细胞中差异表达。和旧的EPC/谱系阴性骨髓细胞（lin-BMC），使用基因组筛选此外，我们已经证明这些miRNA/靶基因分为三个控制的miRNA信号轴。 EPC/lin-BMC的不同基本流程。 ，miR-10A*/miR-21 —↓hmga2 —↑p16Ink4a/p19Arf 主要调控细胞自我更新；miR-146a —↓Plk2 通路主要控制细胞凋亡；miR-29c —↓klf2a —↓miR-126 — ↑ spred-1 —↓VEGF 信号分别主要控制分化。此外，我们已经表明，改变这三种途径可以显着影响 EPC 的衰老以及血管生成和血管修复能力。当前提案的主要目标是了解 HIV 感染对 EPC 和功能的循环水平和功能的影响。我们的中心假设是，HIV 感染与 EPC 衰老有关，这会加速动脉粥样硬化的形成，并且特定的 miRNA 调控网络会介导这一过程，我们将通过检查 EPC 来检验这些原理验证假设。我们将进一步确定候选 miRNA 调控网络在调节 HIV 对 EPC 功能的影响中的作用。了解 EPC 变化以及 HIV 相关加速动脉粥样硬化发病机制的潜在分子机制，可能为促进 HIV 相关心血管疾病新治疗策略的设计开辟一条途径。