MicroRNA regulation of angiogenesis in aging

MicroRNA对衰老过程中血管生成的调节

• 批准号: 10394122
• 负责人: Qingde Wang
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394122
• 关键词: Acute; Affect; Aging; Arteries; Binding; Biological Markers; Blood Vessels; Blood flow; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell Therapy; Cells; Clinical; Data; Defect; Elderly; Endothelial Cells; Family; Functional disorder; Future; Generations; Guanosine Triphosphate; Hindlimb; Impairment; Incidence; Inflammasome; Ischemia; Knowledge; Laboratories; Limb structure; Mediating; Messenger RNA; MicroRNAs; Mitochondria; Modality; Mononuclear; Mus; Organ; Outcome; Outcome Study; Oxidative Stress; Pathway interactions; Patients; Peripheral; Play; Process; Publishing; Reactive Oxygen Species; Recovery; Regulation; Reporting; Risk Factors; Role; Source; Stress; Superoxides; Telomerase; Testing; Therapeutic; Time; Tissues; Translating; Vascular Diseases; Work; age related; aged; angiogenesis; cell age; endothelial repair; endothelial stem cell; improved; limb ischemia; marenostrin; mortality; novel; novel strategies; older patient; receptor; repaired; senescence; stem cell function; tetrahydrobiopterin; tissue repair

Project Summary Impaired vascular repair/angiogenesis is a major clinical problem in aged patients that often leads to ischemic peripheral artery and cardiovascular diseases. Recent studies have focused on strategies to improve aged cells’ angiogenesis capability and subsequent tissue repair. MicroRNAs (miRNAs) have emerged as crucial regulators of vascular function. We propose that altered expression of miRNAs in hind limbs during aging contributes to the age-dependent decline in vascular function. Among the numerous miRNAs, miR-34a has shown promise as a biomarker for organ aging. It correlates with impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease. Remarkably, the mechanism underlying miRNAs’ regulation of angiogenesis, especially in aging, is not completely understood. Our central hypothesis is that the miR-34a retards angiogenesis in aging by directly inhibiting the GCH1/BH4 pathway resulting in excessive oxidative stress, which accelerates senescence, activates inflammasome, and suppresses mitophagy. Remarkably, little information exists on miRNAs regulation of angiogenesis, especially under aging. This hypothesis was formulated after a careful analysis of published work in the field and the generation of some key preliminary data in our laboratory. We plan to test our central hypothesis and accomplish our objective by pursuing three specific aims. In Aim 1, we will establish the critical role of miR-34a in regulation of angiogenesis in aging. Our working hypothesis is that miR-34a inhibits angiogenesis in aging via impairing endothelial progenitor cell (EPC) functions. In Aim 2, we will delineate the effect of the GCH 1/BH4 pathway on miR-34a induced EPC dysfunction in aging. We hypothesize that that miR-34a retards EPC functions in aging by directly inhibiting the GCH1/BH4 pathway, which results in excessive oxidative stress that decreases telomerase activity and accelerates senescence via suppressing Silent Information Regulator 1 (SIRT1). In Aim 3, we will determine how miR-34a affects mitophagy and inflammasome activation in aging after hind limb ischemia. Deficiency of GCH1/BH4 results in elevated reactive oxygen species (ROS) level, which may activate inflammasome, and thus inhibit mitophagy and accelerate the aging process. We hypothesize that miR-34a inhibits mitophagy in aging via Nlrp3 (NOD-like receptor family, pyrin domain containing 3) inflammasome activation, which can be triggered by accumulation of mitochondrial superoxide. The major significance of this study is that it will determine how miRNAs regulate angiogenic functions during aging. Once such knowledge is gained, it is possible that new modalities may be developed to therapeutically rescue impaired angiogenesis in the growing number of aging patients today.

项目概要 血管修复/血管生成受损是老年患者的一个主要临床问题，常常导致缺血 外周动脉和心血管疾病。最近的研究重点是改善老年人的策略 细胞的血管生成能力和随后的组织修复。 MicroRNA (miRNA) 已成为至关重要的 血管功能的调节剂。我们提出衰老过程中后肢 miRNA 的表达发生改变 导致血管功能的年龄依赖性衰退。在众多的 miRNA 中，miR-34a 显示出作为器官衰老生物标志物的前景。它与骨髓来源的功能受损有关 来自心血管疾病患者的单核细胞。值得注意的是，miRNA 的潜在机制 血管生成的调节，特别是在衰老过程中，尚不完全清楚。我们的中心假设是 miR-34a 通过直接抑制 GCH1/BH4 通路来延缓衰老过程中的血管生成，导致过度血管生成 氧化应激会加速衰老、激活炎症小体并抑制线粒体自噬。 值得注意的是，关于 miRNA 调节血管生成的信息很少，尤其是在衰老过程中。这 在对该领域已发表的工作进行仔细分析并产生一些结果后，提出了假设 我们实验室的关键初步数据。我们计划检验我们的中心假设并通过以下方式实现我们的目标 追求三个具体目标。在目标 1 中，我们将确定 miR-34a 在调节中的关键作用 衰老过程中的血管生成。我们的工作假设是 miR-34a 通过损害衰老过程中的血管生成来抑制血管生成 内皮祖细胞 (EPC) 功能。在目标 2 中，我们将描述 GCH 1/BH4 途径的作用 miR-34a 诱导衰老过程中 EPC 功能障碍。我们假设 miR-34a 延迟 EPC 功能 通过直接抑制 GCH1/BH4 通路来延缓衰老，从而导致过度的氧化应激，从而降低 端粒酶活性并通过抑制沉默信息调节器 1 (SIRT1) 加速衰老。在 目标 3，我们将确定 miR-34a 如何影响后肢衰老过程中的线粒体自噬和炎性小体激活 缺血。 GCH1/BH4 缺乏会导致活性氧 (ROS) 水平升高，这可能 激活炎症小体，从而抑制线粒体自噬，加速衰老过程。我们假设 miR-34a通过Nlrp3（NOD样受体家族，含有pyrin结构域3）抑制衰老过程中的线粒体自噬 炎症小体激活，可由线粒体超氧化物的积累触发。主要 这项研究的意义在于它将确定 miRNA 在衰老过程中如何调节血管生成功能。 一旦获得了这些知识，就有可能开发出新的方法来进行治疗性救援 如今，越来越多的老年患者的血管生成受损。

项目成果

Inflammatory cytokine production in a mouse model of Aicardi-Goutieres syndrome and neuroinflammation.

• DOI: 10.4103/1673-5374.335808
• 发表时间: 2022-12
• 期刊: NEURAL REGENERATION RESEARCH
• 影响因子: 6.1
• 作者: Wiley, Clayton;Wang, Qingde
• 通讯作者: Wang, Qingde

An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain.

• DOI: 10.1186/s12974-022-02646-0
• 发表时间: 2022-12-01
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3

ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway.

• DOI: 10.26508/lsa.202101191
• 发表时间: 2022-03
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Guo X;Liu S;Yan R;Nguyen V;Zenati M;Billiar TR;Wang Q
• 通讯作者: Wang Q

ADAR1 Zα domain P195A mutation activates the MDA5-dependent RNA-sensing signaling pathway in brain without decreasing overall RNA editing.

• DOI: 10.1016/j.celrep.2023.112733
• 发表时间: 2023-07-25
• 期刊: Cell reports
• 影响因子: 8.8

Aicardi-Goutières syndrome-associated mutation at ADAR1 gene locus activates innate immune response in mouse brain.

• DOI: 10.1186/s12974-021-02217-9
• 发表时间: 2021-07-31
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Guo X;Wiley CA;Steinman RA;Sheng Y;Ji B;Wang J;Zhang L;Wang T;Zenatai M;Billiar TR;Wang Q
• 通讯作者: Wang Q