Exosomal-mediated pyroptosis in ventilation-associated preterm brain injury

通气相关早产性脑损伤中外泌体介导的细胞焦亡

• 批准号: 10216316
• 负责人: Augusto F Santos Schmidt
• 金额: $ 15.55万
• 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: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216316
• 关键词: Address; Adoptive Transfer; Advisory Committees; Age-Months; Animals; Area; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Bronchopulmonary Dysplasia; CASP1 gene; Caspase; Cell Death; Cell membrane; Cells; Cessation of life; Clinical; Collaborations; Complement; Data; Development; Dyes; Enzyme-Linked Immunosorbent Assay; Face; Fellowship; Foundations; Genetic; Goals; Hyperoxia; Immunohistochemistry; Infant; Inflammation; Inflammatory; Injury; Intervention; Knock-out; Knockout Mice; Knowledge; Label; Laboratories; Life; Link; Low Birth Weight Infant; Lung; Lytic; Mechanical ventilation; Mediating; Medical Students; Mentors; Modeling; Morbidity - disease rate; Mus; Neonatal; Neonatal Brain Injury; Neonatology; Neurodevelopmental Impairment; Neurodevelopmental Problem; Neurons; Newborn Infant; Outcome; Paralysed; Pathogenesis; Pathway interactions; Pediatric Hospitals; Pediatrics; Pharmacology; Physicians; Placebos; Play; Population; Postdoctoral Fellow; Premature Infant; Preterm brain injury; Principal Investigator; Process; Randomized; Rattus; Research; Research Proposals; Residencies; Risk; Rodent; Role; Savings; Scientist; Serum; Survival Rate; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tidal Volume; Time; Training; Training Programs; Universities; Water; Western Blotting; brain cell; career; career development; cytokine; dalton; doctoral student; ex vivo imaging; exosome; genetic approach; high risk infant; improved; inhibitor/antagonist; insight; interest; interleukin-1beta-converting enzyme inhibitor; loss of function; lung injury; mouse model; myelination; neonatal lung injury; neurobehavioral; neurobehavioral test; neuroinflammation; neuron loss; neurosurgery; new therapeutic target; novel; preterm newborn; prevent; professor; pulmonary function; respiratory; skills; student mentoring; ventilation; vesicular release

ABSTRACT This proposal describes a five-year training program and research proposal for the career development of Dr. Augusto Schmidt as a physician-scientist in Neonatology with expertise in neonatal brain injury. Dr. Schmidt completed his Pediatrics residency and Neonatology fellowship at Cincinnati Children’s Hospital and is currently Assistant Professor of Pediatrics in the Division of Neonatology at the University of Miami (UM). Dr. Schmidt is interested in determining the mechanistic relationship between mechanical ventilation and brain injury in preterm newborns, and is particularly interested in how mechanical ventilation causes the lung to release exosomes, which may induce brain cellular death and injury in preterm newborns. Dr. Schmidt will be mentored by Dr. Dalton Dietrich and Dr. Shu Wu with the support of a scientific advisory committee. Dr. Dietrich, a world-renowned expert in brain injury, will mentor Dr. Schmidt’s scientific progress and career development. Dr. Dietrich is the Director of the Miami Project to Cure Paralysis and Distinguished Chair of Neurosurgery at UM and has been committed to training scientists throughout his career having served as the principal investigator of a T32 Training Program, thesis advisor of 9 PhD students, and mentored over 30 postdoctoral fellows. Dr. Wu is a neonatologist and expert in neonatal lung injury and will complement Dr. Dietrich as a co-mentor. Dr. Wu has successfully mentored more than 20 clinical and postdoctoral fellows and medical students. The advisory committee will support Dr. Dietrich and Dr. Wu in mentoring Dr. Schmidt and will consist of Dr. Roberta Brambilla, an expert in neuroinflammation, Dr. Eduardo Bancalari, a neonatologist and expert in neonatal chronic lung disease and Dr. Alan Jobe, a neonatologist and accomplished physician-scientist, who has previously mentored Dr. Schmidt. In this proposal, Dr. Schmidt will test the hypothesis that mechanical ventilation causes the lung to release exosomes containing caspase-1 and that these exosomes cross the blood-brain barrier to activate Gasdermin D (GSDMD) in the brain, inducing cellular death and brain injury. Dr. Schmidt will use a survival model of neonatal rodent ventilation to test the following aims: (1) to determine the mechanistic function of GSDMD in inducing neuronal cell death in ventilation-associated brain injury (VABI); (2) to determine the mechanistic function of pulmonary-derived exosomal caspase-1 in activating neuronal GSDMD in VABI. Dr. Schmidt will use a combination of pharmacological and genetic loss-of function mice models for GSDMD and caspase-1 to address these aims. Brain injury and cellular death will be determined by a combination of techniques including immunohistochemistry, western blotting, ELISA, and real time-PCR. Long-term outcomes will be assessed by neurobehavioral testing. These pharmacological and genetic approaches will delineate the role of the exosomal caspase-1 / neuronal GSDMD pathway in the development of VABI. This research will provide insight into new pathways for therapeutic intervention to prevent or treat brain injury in ventilated preterm newborns and provide the foundation for Dr. Schmidt’s research career focused on neonatal brain injury.

抽象的 该提案描述了一项为期五年的培训计划和研究计划，以实现博士的职业发展。 奥古斯托·施密特（Augusto Schmidt）是新生儿学的身体科学家，在新生儿脑损伤方面具有专业知识。施密特博士 在辛辛那提儿童医院完成了他的儿科住所和新生儿学奖学金 迈阿密大学（UM）的新生儿学科儿科学助理教授。施密特博士是 有兴趣确定早产的机械通气与脑损伤之间的机械关系 新生儿，并且对机械通气如何导致肺部释放外泌体，特别感兴趣， 这可能引起脑细胞死亡和早产儿的损伤。施密特博士将由道尔顿博士考虑 Dietrich和Shu Wu博士在科学咨询委员会的支持下。 Dietrich博士，世界知名的 脑损伤的专家将指导施密特博士的科学进步和职业发展。 Dietrich博士是 迈阿密项目的负责人治愈瘫痪和UM神经外科杰出主席 在整个职业生涯中致力于培训科学家，曾担任T32培训的首席研究员 计划，由9位学生的论文顾问，并指导了30多个博士后研究员。 Wu博士是新生儿学家 以及新生儿肺损伤的专家，并将完成Dietrich博士担任同事。吴博士成功 指导了20多个临床和博士后研究员和医学生。咨询委员会将 支持Dietrich博士和Wu博士在Schmidt博士中，将由Roberta Brambilla博士组成，专家 神经炎症，新生儿医生兼新生儿慢性肺病专家Eduardo Bancalari博士和博士 艾伦·乔布（Alan Jobe）是新生儿学家，并且有成就的身体科学家，他以前曾指导过施密特博士。在 该提案，施密特博士将检验以下假设：机械通气导致肺部释放 包含caspase-1的外泌体和这些外泌体越过血脑屏障以激活加油机 D（GSDMD）在大脑中，诱导细胞死亡和脑损伤。施密特博士将使用新生儿的生存模型 啮齿动物通风以测试以下目的：（1）确定诱导的GSDMD的机械功能 通气相关的脑损伤（VABI）中的神经元细胞死亡； （2）确定 在VABI中激活神经元GSDMD时，肺源性外泌体caspase-1。施密特博士将使用 GSDMD和caspase-1的药物和遗传功能丧失小鼠模型的组合以解决 这些目标。脑损伤和细胞死亡将取决于包括 免疫组织化学，蛋白质印迹，ELISA和实时PCR。长期结果将由 神经行为测试。这些药物和遗传方法将描述外泌体的作用 caspase-1 /神经元GSDMD途径在VABI的发展中。这项研究将提供对新的见解 热干预的途径，以预防或治疗通风早产的脑损伤并提供 施密特博士研究生涯的基础侧重于新生儿脑损伤。