Exosomal Gasdermin D Mediated Lung to Brain Crosswalk in Preterm Brain Injury

外泌体 Gasdermin D 介导早产性脑损伤中的肺至脑交叉

• 批准号: 10373524
• 负责人: SHU WU
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373524
• 关键词: Adoptive Transfer; Age; Air; Alveolar; Animals; Biology; Blood Circulation; Brain; Brain Injuries; Bronchopulmonary Dysplasia; Cell Death; Child Health; Chronic lung disease; Clinical; Communication; Data; Development; Epithelial Cells; Experimental Models; Exposure to; Foundations; Genetic; Goals; Hyperoxia; Impairment; In Vitro; Infant; Inflammasome; Inflammatory; Injury; Lead; Life; Link; Lung; Mediating; Membrane; Modeling; Molecular; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Neurodevelopmental Impairment; Neurons; Newborn Infant; Organ; Outcome; Outcome Study; Oxygen Therapy Care; Pathogenesis; Patients; Pharmacology; Play; Premature Birth; Premature Infant; Premature Infant Diseases; Preterm brain injury; Prospective Studies; Public Health; Pulmonary Surfactant-Associated Protein C; Rattus; Research; Risk; Rodent; Rodent Model; Role; Serum; Severities; Structure; Testing; Therapeutic Intervention; Time; VDAC1 gene; base; blood-brain barrier permeabilization; cohort; effective therapy; exosome; extracellular vesicles; impaired brain development; improved; in vivo; inhibitor/antagonist; knockout gene; loss of function; lung development; lung injury; nano-exosomes; nanosized; nerve stem cell; neurodevelopment; neuropathology; novel; postnatal; preclinical study; prevent; respiratory; response; uptake

PROJECT SUMMARY Bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development is the most common morbidity complicating preterm birth, and a predictor of poor neurodevelopmental outcomes. Currently it is unclear to what extent lung injury contributes to neurodevelopmental impairment (NDI) in these preterm infants. Based on our preliminary data which demonstrate that circulating exosomes derived from preterm infants who develop severe BPD induce neural stem cell (NSC) death in vitro, the major goal of this proposal is to determine the molecular mechanisms by which these circulating exosomes mediate lung to brain crosstalk and their contribution to brain injury and NDI. Understanding these mechanisms is fundamental to public health as more preterm infants are surviving, yet there remains no effective therapy for either BPD or its associated NDI. Pyroptosis is a newly described form of inflammatory cell death that is solely regulated by gasdermin D (GSDMD), an inflammasome-activated membrane “pore-forming” protein. Exosomes are nano- sized extracellular vesicles that play a key role in inter-organ communications. We recently demonstrated that preterm infants who develop severe BPD have increased expression of GSDMD and surfactant protein C (SPC), a marker of alveolar type II epithelial cells (AEC), in their circulating exosomes at 1 week of age. In preclinical studies with an experimental model of BPD, similar GSDMD-containing exosomes were isolated from the serum of newborn rats exposed to hyperoxia. Importantly, adoptive transfer of these exosomes into the circulation of normal newborn rats impaired brain development. These findings lead us to propose a novel model that links BPD, exosomal GSDMD and brain injury. The central hypothesis of this model is that GSDMD-containing exosomes are released from AEC into the circulation during the evolving stage of BPD, and neuronal uptake of these exosomes results in neural cell pyroptosis and NDI. This hypothesis will be tested through three aims: Aim 1. To characterize the relationship between GSDMD expression profiles in AEC-derived circulating exosomes and the severity of BPD in preterm infants. Aim 2. To determine the mechanistic functions of circulating exosomes from preterm infants in inducing brain injury and NDI. Aim 3. To elucidate the molecular mechanisms by which hyperoxia stimulates AEC to release GSDMD+ exosomes that induce brain injury and NDI. These studies will delineate a novel exosomal GSDMD-mediated lung to brain crosstalk that is critical in the pathogenesis of brain injury and NDI in premature infants. Completion of this project will provide a strong foundation to further explore therapeutic interventions that target exosomal GSDMD to improve long-term respiratory and neurodevelopment outcomes in these infants. This proposal is aligned with the overarching goal of the NICHD and NHLBI that is to improve children’s health through cutting edge research and it will be executed by a team approach with experts in clinical and basic respiratory research, neuropathology, and exosome and GSDMD biology.

项目摘要 以炎症性损伤和肺发育受损为特征的支气管肺发育不良（BPD）是 最常见的发病率使早产复杂化，并且是神经发育结果不良的预测指标。 目前尚不清楚肺损伤在多大程度上导致神经发育障碍（NDI） 早产婴儿。基于我们的初步数据，该数据表明循环外泌体从 发生严重BPD的早产婴儿在体外诱导神经元干细胞（NSC）死亡，这是主要目标 建议是确定这些循环外泌体培养基到大脑的分子机制 串扰及其对脑损伤和NDI的贡献。了解这些机制对于 公共卫生随着越来越早的婴儿的生存，但对BPD或ITS尚无有效的疗法 相关的NDI。凋亡是一种新描述的炎性细胞死亡形式，仅由 Gasdermin D（GSDMD），一种炎症体激活的膜“形成孔”蛋白。外泌体是纳米 - 大小的细胞外蔬菜在器官间通信中起关键作用。我们最近证明了 发生严重BPD的早产婴儿的GSDMD和表面活性剂蛋白C（SPC）的表达增加， 1周龄时的循环外泌体中，肺泡II型上皮细胞（AEC）的标志物。在临床前 通过BPD实验模型的研究，从串行中分离出类似的含GSDMD的外泌体 暴露于高氧的新生大鼠。重要的是，这些外泌体的自适应转移到循环中 正常的新生大鼠损害了大脑发育。这些发现使我们提出了一个新的模型，该模型与 BPD，外泌体GSDMD和脑损伤。该模型的中心假设是含GSDMD 在BPD的发展阶段，外泌体从AEC释放到循环中，以及神经元的摄取 这些外泌体导致神经细胞凋亡和NDI。该假设将通过三个目标进行检验：目标 1。表征AEC衍生的循环外泌体中GSDMD表达曲线之间的关系 以及早产儿中BPD的严重程度。目标2。确定循环的机械功能 早产儿诱导脑损伤和NDI的外泌体。目标3。阐明分子机制 高氧刺激AEC释放影响脑损伤和NDI的GSDMD+外泌体。这些 研究将描绘出一种新型的外泌体GSDMD介导的肺部对脑串扰，这对 早产儿的脑损伤和NDI的发病机理。该项目的完成将提供强大的 进一步探索靶向外泌体GSDMD的热干预措施的基础 这些婴儿的呼吸和神经发育结果。该提议与总体目标保持一致 通过尖端研究改善儿童健康的NICHD和NHLBI，将执行 通过与临床和基本呼吸研究，神经病理学和外泌体和外部研究专家的团队态度 GSDMD生物学。