Neuroimmune axis contribution to the pathophysiology of pulmonary hypertension

神经免疫轴对肺动脉高压病理生理学的贡献

• 批准号: 10664323
• 负责人: Aline Cristina Oliveira
• 金额: $ 13.31万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664323
• 关键词: Ablation; Animal Model; Area; Arrhythmia; Attenuated; Brain; Brain region; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cell Communication; Cells; Central Nervous System; Cessation of life; Chronic; Data; Development; Disease; Disease associated microglia; Dysautonomias; Epigenetic Process; Etiology; Evaluation; Experimental Models; Exposure to; Flow Cytometry; Functional disorder; Gene Expression; Genetic Models; Genetic Techniques; Goals; Heart; Hematopoietic; Hematopoietic stem cells; Hypothalamic structure; Immune; Immunohistochemistry; Infiltration; Inflammatory; Knockout Mice; Lung; Mentors; Mentorship; Methodology; Microglia; Mus; Myelogenous; Myeloid Cells; Neuroanatomy; Neuroimmune; Neuronal Plasticity; Neurons; Nucleus solitarius; Organ; Outcome; Output; Pathogenicity; Patients; Pharmacotherapy; Phase; Phenotype; Predisposing Factor; Prognosis; Progressive Disease; Publishing; Pulmonary Hypertension; Research; Scientist; Series; Severities; Slice; Sympathetic Nervous System; TREM2 gene; Techniques; Testing; Therapeutic; Training; Up-Regulation; Ventricular Dysfunction; attenuation; drug development; experience; experimental study; gene function; hypoxia-induced pulmonary hypertension; improved; innovation; insight; member; mortality; neuroinflammation; neurotransmission; novel; paraventricular nucleus; professor; programs; respiratory; right ventricular failure; single-cell RNA sequencing; systemic inflammatory response; targeted treatment; therapeutic target; therapy development; two photon microscopy; vasoconstriction

PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a progressive disease leading to right heart failure and an unacceptably high mortality rate. Despite major milestones in our understanding of predisposing factors to PH, to date, we still have limited mechanistic insight into its development and progression. Thus, despite advances in current therapies, there is no available cure and treatment has limited improvement in outcome. Therefore, development of drug treatments with alternate targets may benefit patients. To this end, our published and preliminary studies demon- strate increased activated microglia, specifically TREM2-expressing disease-associated microglia, contribute to neuroinflammation in autonomic brain regions, particularly the paraventricular nucleus (PVN) of the hypothala- mus. These data informed our central hypothesis that activation of resident microglia, especially TREM2+ microglia subtype and infiltrated myeloid precursors, promotes aberrant preautonomic neuronal signal- ing in the paraventricular nucleus of the hypothalamus leading to sustained sympathetic activation, which is critical to PH. We plan to test this hypothesis via the following three aims: Aim 1 will evaluate the microglia-dependent mechanisms that contribute to increased preautonomic neuron activity within the PVN; Aim 2 will evaluate the mechanism by which TREM2 contributes to PH pathophysiology, exploring the working hy- pothesis that TREM2 expression within microglia is necessary and sufficient for augmented sympathetic activity and thus, a potential therapeutic targeted. Finally, Aim 3 will test the hypothesis that chronic microglia activation leads to dysautonomia and enhanced systemic inflammation, with consequently increase in circulating myeloid cells infiltration to autonomic brain regions such as PVN, contributing to neuroinflammation in a feedforward loop, worsening PH outcomes. Experiments will combine 2-photon microscopy in brain slices, flow cytometry, sympa- thetic ablation, and several cutting-edge genetic models. Ultimately, we expect results of these studies to con- tribute to better understanding of the mechanism whereby microglia and infiltrated myeloid precursors contribute to the pathophysiology of PH. Collectively, the proposed studies will lead to novel information regarding the brain’s pathogenic contribution to pulmonary hypertension, which may represent an entirely novel target for PH therapeutics. In addition, strong mentorship by Drs. Andrew Bryant and Eric Krause, as well as a Mentoring Committee comprised of established professors, who are experts in the proposed techniques and have extensive mentoring experience; will provide conceptual and methodological training, to achieve the research goals and prepare me to establish an independent research program.

项目摘要/摘要 肺动脉高压（pH）是一种进行性疾病，导致右心力衰竭，无法接受 死亡率。尽管我们对pH值的易感性因素的理解中有很大的里程碑，但迄今为止，我们仍然有 对其发展和进展的机械洞察力有限。那是目前疗法的目的地进展， 没有可用的治愈方法，治疗的结果有限。因此，药物的发展 具有替代靶标的治疗可能使患者受益。为此，我们发表和初步的研究恶魔 - 策略增加了活化的小胶质细胞，特别是表达疾病相关的小胶质细胞，有助于 自主脑区域中的神经炎症，特别是下丘脑的室室核（PVN） mus。这些数据介绍了我们的中心假设，即居民小胶质细胞的激活，尤其是trem2+ 小胶质细胞亚型和浸润的髓样前体，促进异常的预述神经元信号 - 在下丘脑的室室核中，导致持续的交感神经激活， 这对pH至关重要。我们计划通过以下三个目标检验这一假设：AIM 1将评估 小胶质细胞依赖性机制有助于增加PVN中的预据自主神经元活性；目的 2将评估TREM2有助于pH病理生理学的机制，探索工作的工作 小胶质细胞中的trem2表达是必要的，足以增强交感神经活动 因此，一种潜在的治疗目标。最后，AIM 3将检验慢性小胶质细胞激活的假设 导致功能障碍和系统性炎症增强，因此循环髓样 细胞浸润到诸如PVN之类的自主神经区域，导致喂食循环中的神经炎症， 恶化的pH结果。实验将在脑切片，流式细胞仪，综合体中结合2光子显微镜检查 Thetic消融和几种尖端的遗传模型。最终，我们期望这些研究的结果能够解决 致敬，以更好地理解小胶质细胞和浸润的髓样前体的机制有助于 pH的病理生理学。拟议的研究总体而言，将导致有关该研究的新信息 大脑对肺动脉高压的致病贡献，这可能代表了PH的完全新颖的靶标 治疗。此外，博士的强大精神训练。安德鲁·布莱恩特（Andrew Bryant）和埃里克·克劳斯（Eric Krause）以及指导 委员会完成了既定教授，他们是拟议技术的专家 指导经验；将提供概念和方法学培训，以实现研究目标和 为我准备建立独立的研究计划。