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）感染加速细胞和生物体衰老，并显著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，并可预测心血管事件。衰老的EPC具有受损的修复能力，这与动脉粥样硬化的发展有关。HIV感染对EPC的影响及其机制尚不清楚。MicroRNA（miRNA）调控体干细胞的衰老。我们已经使用基因组筛选鉴定了miR-10A *、miR-21、miR-146 a、miR-29 c和miR-126以及它们的靶基因在年轻和老年EPC/谱系阴性骨髓细胞（lin-BMC）中差异表达。此外，我们已经证明，这些miRNA/靶基因分离成三个miRNA信号传导轴，控制EPC/lin-BMC的不同基本过程。 具体而言，miR-10A */miR-21-↓ hmga2-↑ p16 Ink4a/p19 Arf主要调控细胞自我更新; miR-146 a-↓ Plk2通路主要调控细胞凋亡; miR-29 c-↓ klf2a-↓ miR-126-↑ spred-1-↓ VEGF信号通路主要调控分化。此外，我们已经表明，修改这三个途径可以显着影响衰老和血管生成和血管修复能力的EPC。本研究的主要目的是了解HIV感染对EPC循环水平和功能的影响及其潜在机制。我们的中心假设是，HIV感染与EPC衰老有关，这有助于加速动脉粥样硬化形成，并且特定的miRNA调控网络介导了这一过程。我们将通过使用多种标准化方法/技术检查充分表征的临床样本中的EPC水平并使用已建立的细胞培养程序测试其功能来测试这些原理验证假设。我们将进一步确定候选miRNA调控网络在介导HIV对EPC功能影响中的作用。这些研究的结果将提供对EPC变化和HIV相关加速动脉粥样硬化发病机制中的潜在分子机制的理解，并可能为促进HIV相关心血管疾病的新治疗策略的设计开辟途径。