Project 3: Albayram

项目3：阿尔拜拉姆

• 批准号: 10556544
• 负责人: Onder Albayram
• 金额: $ 22.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556544
• 关键词: Adolescence; Adult; Affect; Applications Grants; Area; Behavioral; Brain; Brain Injuries; CD11c Antigens; Cells; Centers of Research Excellence; Cerebral Palsy; Chronic; Cognitive; Complement; Complement 3a; Complement Activation; Complement Receptor; Data; Data Set; Development; Disease; Ensure; Failure; Functional disorder; Future; Goals; Hemorrhage; Hydrocephalus; ITGAM gene; ITGAX gene; ITGB2 gene; Immune; Immunologic Memory; Infiltration; Injury; Knockout Mice; Knowledge; Life; Ligands; Link; Macrophage-1 Antigen; Mediating; Medical; Mentors; Microglia; Modeling; Mus; Neonatal; Neonatal Brain Injury; Nerve Degeneration; Neurodevelopmental Deficit; Neurodevelopmental Disorder; Neurodevelopmental Impairment; Neuroimmune; Neurons; Opsonin; Pathogenicity; Pathologic Processes; Perinatal subependymal hemorrhage; Periventricular Leukomalacia; Phagocytosis; Phase; Phenotype; Process; Research Personnel; Research Support; Resources; Risk; Risk Factors; Risk Reduction; Role; Signal Transduction; Site; Subependymal; Symptoms; Synapses; Testing; Therapeutic; Time; Training; United States National Institutes of Health; Vascularization; associated symptom; behavioral impairment; brain cell; career development; cell type; clinically relevant; fetal; immune activation; innovation; intraventricular hemorrhage; mouse model; neonatal brain; neonate; neurobehavioral; neurodevelopment; neuroinflammation; novel; pharmacologic; preterm newborn; receptor; response; success; tool; uptake

PROJECT 3 – PROJECT SUMMARY Aberrant secondary immune activity after brain injury during neonatal life affects critical phases of brain development, with long-lasting behavioral abnormalities relevant to neurodevelopmental disorders. The most common form of brain injury in the preterm neonate is germinal matrix hemorrhage (GMH), which may display pathophysiological alterations relating to risk factors for atypical brain development. However, very little is known about how an aberrant secondary immune response that occurs and persists in the higher-order cortical and limbic regions of the developing brain following GMH leads to failure of compensatory synaptic and neuronal mechanisms and contributes to behavioral abnormalities. Recent studies have revealed a central role for complement in serving as a local immune recognition mechanism that promotes secondary injury after brain injury. Our preliminary data indicate a similar role for complement in propagating the pathogenic sequelae of GMH. Using a mouse model of GMH, we will investigate how complement dependent neuroinflammation in the neonatal brain following injury leads to failure of compensatory synaptic and neuronal mechanisms in primary cognitive centers of the brain. We will determine how complement activation impacts long-term behavioral changes relevant to neurodevelopment disorders, and we will investigate complement inhibition as a potential therapeutic approach to mitigate the pathogenic sequelae of GMH. Additionally, we will investigate the role of aberrant neuron/synapse elimination in the propagation of secondary brain injury, and specifically investigate a role for complement opsonin-complement receptor interactions in this process. The CNDD will provide me with critical support for the project through access to CNDD Cores and financial resources to support the research efforts, and the career development and mentoring activities will ensure future success in obtaining an NIH R01 within a 3-year period and a transition to an established investigator in the field of NDDs.

项目3 ----项目概要 新生儿脑损伤后异常的继发性免疫活动影响脑的关键期 发育，与神经发育障碍相关的长期行为异常。最 早产儿脑损伤的常见形式是老年性基质出血（GMH）， 与非典型脑发育的危险因素有关的病理生理学改变。然而， 关于异常的次级免疫反应是如何发生并持续在高级皮质和 GMH后发育中的大脑边缘区导致代偿性突触和神经元功能的丧失， 导致行为异常。最近的研究表明， 补体作为局部免疫识别机制，促进脑损伤后的继发性损伤 损伤我们的初步数据表明，补体在传播的致病性后遗症， GMH使用小鼠GMH模型，我们将研究补体依赖性神经炎症在GMH中的作用。 新生儿脑损伤导致原发性脑损伤后代偿性突触和神经元机制的失败， 大脑的认知中心。我们将确定补体激活如何影响长期行为 与神经发育障碍相关的变化，我们将研究补体抑制作为一种潜在的 治疗方法，以减轻GMH的致病性后遗症。此外，我们还将研究 在继发性脑损伤的传播中异常神经元/突触消除，并特别研究 补体调理素-补体受体相互作用在这一过程中的作用。全国民主与发展委员会将为我提供 通过获得CNDD核心和财政资源来支持研究，为项目提供关键支持 努力，职业发展和指导活动将确保未来成功获得NIH R 01 在3年内，并过渡到一个既定的调查员在该领域的国家失踪人口。