PGI2 restrains immunopathogenesis in hypertension

PGI2 抑制高血压的免疫发病机制

基本信息

批准号：
10731402
负责人：
Allison Elizabeth Norlander
金额：
$ 24.9万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731402
关键词：
Adaptive Immune System Address Adult Affect Allergic inflammation American Angiotensin II Anti-Inflammatory Agents Antigen Presentation Aorta Arachidonic Acids Award Biological Availability Blood Pressure Blood Vessels Cardiovascular Diseases Cardiovascular system Cell physiology Cells Coxibs 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 Innate Immune System Invaded Journals Kidney Knockout Mice Laboratories Lead Lipids Macrophage Maps Mentors Metabolic Pathway Modeling Morbidity - disease rate Mus Organ 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 cell infiltration T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Th2 Cells Therapeutic Thromboxanes Training Treprostinil United States Vascular Diseases Vasoconstrictor Agents Wild Type Mouse analog blood pressure control blood pressure elevation career career development cell type clinical investigation clinical translation clinically significant cyclooxygenase 2 cytokine eicosanoid metabolism high salt diet hypertension control hypertension treatment hypertensive immunoregulation monocyte mortality mouse model normotensive novel novel therapeutics prevent programs receptor response restraint transcriptome sequencing vascular inflammation

项目摘要

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.

项目概要高血压是指血压高于130/80mmHg的疾病。高血压显着增加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，但我们仍然远未了解其真正的病因高血压。近年来，炎症被确定在高血压中起因果作用。具体来说，免疫细胞在疾病过程中侵入靶器官并释放细胞因子，导致最终器官损伤。多项研究已确定树突状细胞 (DC) 和单核细胞的抗原呈递对于高血压的发生很重要。此外，促炎性 T 细胞会使疾病持续存在。反对- 炎症性T调节细胞（Treg）可以控制高血压反应。有趣的是，有证据表明长期使用环氧合酶抑制剂，可防止花生四烯酸（AA）代谢前列腺素和血栓素会增加血压。前列腺素 I2 (PGI2) 是一种 AA 代谢物，我们的实验室已确定具有免疫调节作用。我们的小组已经证明 PGI2 的作用是直接抑制促炎 DC 和 CD4+ Th1 和 Th2 细胞的功能，同时促进耐受性 DC 的功能。然而，PGI2 对高血压患者免疫细胞功能的影响尚不清楚。未知。先前的一项研究表明，缺乏 PGI2 受体的小鼠，IP 的发展水平升高高盐饮食引起的血压升高，表明 PGI2 信号对于控制血液很重要对刺激作出反应的压力升高。此外，我有初步数据表明 PGI2 控制对高血压刺激的炎症反应。具体来说，IP 缺陷的小鼠的浸润增加与野生型 (WT) 小鼠相比，T 细胞进入主动脉以响应血管紧张素 II (Ang II)。此外，在 Ang II 输注过程中输注 PGI2 类似物曲前列环素可防止 T 细胞浸润，与接受 Ang II 和 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让我假设 PGI2 在高血压期间促进抗炎反应。为了检验这个假设，我们将使用高血压小鼠模型以及来自正常血压和高血压小鼠和人类的原代细胞：目标 1 (K99)：检验 PGI2 在高血压期间促进 Treg 功能和稳定性的假设，从而对抗 T 细胞的促炎亚群；目标 2 (R00)：检验假设 PGI2 在高血压期间抑制促炎性 DC 并促进耐受性 DC 功能。确定 PGI2 控制高血压免疫反应的机制将极大地帮助推进该领域的发展并为高血压治疗带来新的治疗方向。这些建议研究以及我提出的职业发展计划将为我的职业生涯奠定基础独立调查员在优越的环境中。