PGI2 restrains immunopathogenesis in hypertension

PGI2 抑制高血压的免疫发病机制

• 批准号: 10282751
• 负责人: Allison Elizabeth Norlander
• 金额: $ 13.8万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10282751
• 关键词: Adaptive Immune System; Address; Adult; Affect; Allergic inflammation; American; Angiotensin II; Anti-Inflammatory Agents; Antigen Presentation; Antigens; Aorta; Arachidonic Acids; Award; Biological Availability; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Cyclooxygenase Inhibitors; Data; Dendritic Cells; Development; Development Plans; Disease; Disease Progression; Disease model; Environment; Enzymes; Epoprostenol; Etiology; Experimental Models; FDA approved; Foundations; Gene Expression Profile; Human; Hypertension; Immune; Immune response; Immune system; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Invaded; Journals; Kidney; Knockout Mice; Laboratories; Lead; Lipids; Mentors; Metabolic Pathway; Modeling; Morbidity - disease rate; Mus; Organ; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Production; Property; Prostaglandin Receptor; Prostaglandins; Publications; Pulmonary Hypertension; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Site; Stimulus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Th2 Cells; Therapeutic; Thromboxanes; Training; Treprostinil; Tumor-infiltrating immune cells; United States; Vascular Diseases; Vasoconstrictor Agents; Wild Type Mouse; analog; blood pressure regulation; career; career development; cell type; clinical investigation; clinically significant; cyclooxygenase 2; cytokine; eicosanoid metabolism; high salt diet; hypertension control; hypertension treatment; immune function; immunoregulation; inhibitor/antagonist; kidney vascular structure; macrophage; monocyte; mortality; mouse model; normotensive; novel; novel therapeutics; prevent; programs; receptor; response; transcriptome sequencing; vascular inflammation

PROJECT SUMMARY Hypertension is a disease defined as blood pressure that is greater than 130/80mmHg. Hypertension contributes significantly to cardiovascular disease morbidity and mortality. While the importance of blood pressure control has become abundantly clear, we are still far from understanding the true etiology of hypertension. In recent years, inflammation was determined to play a causal role in hypertension. Specifically, immune cells invade target organs during the course of the disease and release cytokines that cause end- organ damage. Several studies have determined antigen presentation by dendritic cells (DCs) and monocytes is important for initiation of hypertension. In addition, pro-inflammatory T cells perpetuate the disease. Anti- inflammatory T regulatory cells (Treg) can control the hypertensive response. Interestingly, evidence suggests that long-lasting use of cyclooxygenase inhibitors, which prevent metabolism of arachidonic acid (AA) to prostaglandins and thromboxane, increases blood pressure. Prostaglandin I2 (PGI2) is an AA metabolite that our laboratory has determined has immunomodulatory effects. Our group has demonstrated that PGI2 acts to directly inhibit the functionality of pro-inflammatory DCs and CD4+ Th1 and Th2 cells, while promoting the function of tolerogenic DCs. However, the impact of PGI2 on the functionality of immune cells in hypertension is unknown. A previous study has demonstrated that mice deficient in the receptor for PGI2, IP, develop elevated blood pressure in response to high salt diet, suggesting that PGI2 signaling is important for controlling blood pressure elevation in response to stimuli. Further, I have preliminary data which suggests that PGI2 controls the inflammatory response to hypertensive stimuli. Specifically, mice deficient in IP have increased infiltration of T cells into their aortas compared to wild-type (WT) mice in response to angiotensin II (Ang II). In addition, infusion of the PGI2 analog treprostinil during the course of Ang II infusion prevents the infiltration of T cells, monocytes/macrophages and DCs into the aorta of WT mice compared to WT mice that received Ang II and the vehicle for treprostinil. Thus, these recent studies and my preliminary data lead me to hypothesize that PGI2 promotes anti-inflammatory responses during hypertension. To test this hypothesis we will use mouse models of hypertension and primary cells from normotensive and hypertensive mice and humans to: Aim 1 (K99): Test the hypothesis that PGI2 promotes Treg function and stability during hypertension, thereby counteracting pro-inflammatory subsets of T cells; and Aim 2 (R00): Test the hypothesis that PGI2 restrains pro-inflammatory DC and promotes tolerogenic DC function during hypertension. Determining the mechanisms by which PGI2 controls the immune response to hypertension will greatly advance the field and result in new therapeutic directions for the treatment of hypertension. These proposed studies, along with my proposed career development plan, will provide a foundation for my career as an independent investigator in an outstanding environment.

项目摘要 高血压是一种疾病，定义为血压大于130/80 mmHg。高血压 心血管疾病的发病率和死亡率。虽然血液的重要性 压力控制已经变得非常清楚，我们仍然远远没有了解真正的病因， 高血压近年来，炎症被确定为在高血压中起因果作用。具体地说， 免疫细胞在疾病过程中侵入靶器官并释放细胞因子， 器官损伤一些研究已经确定了树突状细胞（DC）和单核细胞的抗原呈递 是引发高血压的重要因素。此外，促炎性T细胞使疾病永久化。反 炎症性T调节细胞（Treg）可以控制高血压反应。有趣的是，证据表明 长期使用环氧合酶抑制剂，其防止花生四烯酸（AA）代谢， 前列腺素和血栓素，增加血压。前列腺素I2（PGI 2）是AA代谢物， 我们的实验室已经确定它具有免疫调节作用。我们的研究小组已经证明，PGI 2的行为， 直接抑制促炎DC和CD 4 + Th 1和Th 2细胞的功能，同时促进 致耐受性DC的功能。然而，PGI 2对高血压患者免疫细胞功能的影响， 未知先前的研究表明，PGI 2受体IP缺陷的小鼠， 高盐饮食对血压的影响，表明PGI 2信号对控制血压很重要。 对刺激作出反应的压力升高。此外，我有初步的数据表明，PGI 2控制 对高血压刺激的炎症反应。具体而言，IP缺陷的小鼠具有增加的浸润， 与野生型（WT）小鼠相比，T细胞进入它们的睾丸，对血管紧张素II（Ang II）的反应。此外，本发明还提供了一种方法， 在Ang II输注过程中输注PGI 2类似物曲前列环素防止T细胞的浸润， 与接受Ang II的WT小鼠相比，单核细胞/巨噬细胞和DC进入WT小鼠的主动脉， 曲前列环素的载体。因此，这些最近的研究和我的初步数据使我假设， PGI 2在高血压期间促进抗炎反应。为了验证这一假设，我们将使用 高血压小鼠模型和来自血压正常和高血压小鼠和人的原代细胞： 目的1（K99）：检验PGI 2在高血压期间促进Treg功能和稳定性的假设， 从而抵消T细胞的促炎亚群;以及目标2（R 00）：检验以下假设： PGI 2抑制促炎性DC并促进高血压期间致耐受性DC功能。 确定PGI 2控制高血压免疫反应的机制将大大有助于 推进该领域，并为高血压的治疗提供新的治疗方向。这些拟议 学习，沿着我的职业发展计划，将为我的职业生涯提供一个基础， 独立调查员在出色的环境。