Role of sensory nerves in perivascular inflammation and vasomotor dysfunction with inflammatory bowel disease

感觉神经在炎症性肠病血管周围炎症和血管舒缩功能障碍中的作用

• 批准号: 10586064
• 负责人: Erika Mary Boerman
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586064
• 关键词: Address; Adipose tissue; Affect; Arteries; Atrophic; Binding; Biochemical; Biological Assay; Blood Vessels; Blood flow; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cannulations; Capsaicin; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Colitis; Colonic inflammation; Defect; Denervation; Development; Disease; Endothelial Cells; Endothelium; Excision; Flow Cytometry; Follow-Up Studies; Functional disorder; Health; Helicobacter; Helicobacter hepaticus; Histologic; Image; Image Cytometry; Immune; Immune response; Impairment; Incidence; Infiltration; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Lasers; Link; LoxP-flanked allele; Macrophage; Macrophage Activation; Measures; Mediating; Mesenteric Arteries; Mesentery; Mus; Nerve; Neuroimmune; Neuropeptides; Neurotransmitters; Pathogenesis; Pathway interactions; Patients; Peptide Receptor; Perfusion; Population; Preparation; Quality of life; Recurrence; Research; Role; Sensory; Severities; Severity of illness; Signal Pathway; Signal Transduction; Smooth Muscle; Substance P; TACR1 gene; Testing; Therapeutic; Transgenic Mice; Tunica Adventitia; Vascular Diseases; Vasodilation; Vasomotor; Visualization; Work; adipokines; afferent nerve; blood flow measurement; cardiovascular disorder risk; chemokine; comorbidity; confocal imaging; constriction; cytokine; electric field; gut inflammation; improved; in vivo; insight; mouse model; neurotransmitter release; peptide P; prevent; receptor; transcriptome sequencing; vascular inflammation; vasoconstriction

Project Summary and Abstract Inflammatory Bowel Disease (IBD) is an increasingly prevalent chronic disease marked by aberrant immune responses and intestinal and extra-intestinal inflammation. IBD is comorbid with cardiovascular disease and associated with decreased blood flow to the intestines, with a critical but poorly-studied role for the mesenteric (MAs) arteries that regulate intestinal perfusion. Perivascular sensory nerves (PSNs) continuously innervate the MA adventitia and perivascular adipose tissue (PVAT), regulating vasomotor function and facilitating blood flow by dilating MAs and inhibiting sympathetic vasoconstriction. With IBD, these PSN functions are severely impaired, and the PVAT that is normally anticontractile becomes procontractile through an unknown mechanism, further impairing MA dilation. The sensory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) may also be important in these IBD-related vascular dysfunctions, as they are linked to disease severity and can mediate perivascular neuro-immune and neuro-adipose signaling through activation of local immune cells. Previous work demonstrates that macrophages accumulate in both the MA adventitia and PVAT during IBD, and macrophage depletion restores the ability of PSNs to dilate MAs and inhibit sympathetic constriction. This suggests that perivascular macrophages can modulate arterial function with IBD, likely through a mechanism involving sensory neurotransmitters in the adventitia and PVAT. What remains unclear is how macrophages participate in PSN, PVAT, and blood flow dysfunction and when these changes occur in IBD development. This project will test the overall hypothesis that PSN neurotransmitter released in adventitia and PVAT of MAs promotes macrophage activation, accumulation, and inflammatory mediator release, leading to vasomotor defects and impaired blood flow early in IBD pathogenesis. To investigate these relationships, the immune-driven, Helicobacter hepaticus-induced IL10-/- mouse model of IBD will be used to address 3 research Aims. Aim 1 will use confocal imaging, flow cytometry, and in vivo blood flow measurements at timepoints throughout IBD development to determine when macrophage infiltration causes PSN and PVAT dysfunction and impairs blood flow compared to the development of colon inflammation. Aim 2 will use sensory denervation and transgenic mice lacking PVAT in conjunction with isolated artery preparations to determine whether the presence and activity of PSNs and/or PVAT drive macrophage infiltration around MAs with IBD. Aim 3 will use advanced imaging, primary adventitial and PVAT macrophages, and biochemical assays to test whether sensory neuropeptides can activate macrophages from the MA adventitia and PVAT to release inflammatory mediators. This project will uniquely define the role of PSNs and their signaling pathways in neuro-immune-adipose interactions mediating vasomotor function, and it will determine how these pathways are affected during the pathogenesis of IBD. Results will provide new insight towards developing selective therapeutic strategies for treating vascular dysfunction and impaired intestinal blood flow to improve quality of life for IBD patients.

项目概要和摘要 炎症性肠病（IBD）是一种日益流行的慢性疾病，其特征是异常的免疫反应， 反应以及肠道和肠外炎症。IBD与心血管疾病共病， 与肠道血流量减少有关，肠系膜血管的作用至关重要，但研究甚少。 (MAs)调节肠道灌注的动脉。血管周围感觉神经（PSNs）持续支配血管周围神经。 MA外膜和血管周围脂肪组织（PVAT），调节血管功能并促进血流 通过扩张动脉瘤和抑制交感神经血管收缩。在IBD中，这些PSN功能严重受损， 受损，并且正常情况下抗收缩的PVAT通过未知机制变得促收缩， 进一步损害MA扩张。感觉神经肽降钙素基因相关肽（CGRP）和物质 P（SP）在IBD相关的血管功能障碍中也可能很重要，因为它们与疾病的严重程度有关 并可通过激活局部免疫细胞介导血管周围神经免疫和神经脂肪信号传导， 细胞以前的工作表明，巨噬细胞在MA外膜和PVAT中积累， IBD，巨噬细胞耗竭恢复PSN扩张MA和抑制交感神经收缩的能力。 这表明血管周围巨噬细胞可以调节IBD的动脉功能，可能是通过 涉及外膜和PVAT中感觉神经递质的机制。目前尚不清楚的是 巨噬细胞参与PSN，PVAT和血流功能障碍，当这些变化发生在IBD 发展本项目将检验PSN神经递质在外膜释放的总体假设， MAs的PVAT促进巨噬细胞活化、积聚和炎症介质释放，导致 IBD发病早期的血管缺陷和血流受损。为了研究这些关系， 免疫驱动、肝螺杆菌诱导的IL 10-/-IBD小鼠模型将用于3项研究 目标。目的1将使用共聚焦成像，流式细胞术，并在体内血流测量的时间点 以确定巨噬细胞浸润何时引起PSN和PVAT功能障碍， 与结肠炎症的发展相比会损害血流。目标2将使用感觉去神经支配， 缺乏PVAT的转基因小鼠与分离的动脉制备物结合，以确定是否存在 并且PSN和/或PVAT的活性驱动具有IBD的MA周围的巨噬细胞浸润。目标3将使用先进的 成像，原发性外膜和PVAT巨噬细胞，以及生化测定，以测试感觉 神经肽可以激活来自MA外膜和PVAT的巨噬细胞以释放炎性介质。 该项目将独特地定义PSN及其信号通路在神经免疫脂肪中的作用 相互作用介导的血管功能，它将确定如何在这些途径的影响， IBD的发病机制结果将为开发选择性治疗策略提供新的见解， 治疗血管功能障碍和肠血流受损，以改善IBD患者的生活质量。