Project 3: Albayram

项目3：阿尔拜拉姆

基本信息

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
项目类别：
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

项目摘要

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 – 项目摘要新生儿脑损伤后异常的次级免疫活动影响大脑的关键阶段发育，具有与神经发育障碍相关的长期行为异常。早产儿脑损伤的常见形式是生发基质出血 (GMH)，可能会表现出然而，与非典型大脑发育的危险因素有关的病理生理学改变却知之甚少。关于异常的次级免疫反应如何在高阶皮质和 GMH 后大脑边缘区域的发育导致代偿性突触和神经元的衰竭最近的研究揭示了行为异常的核心作用。补体作为局部免疫识别机制，促进脑后继发性损伤我们的初步数据表明补体在传播致病性后遗症中具有类似的作用。使用 GMH 小鼠模型，我们将研究补体依赖性神经炎症如何在损伤后的新生儿大脑会导致原发性代偿性突触和神经机制失效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潜在的此外，我们将研究减轻 GMH 致病后遗症的治疗方法。继发性脑损伤传播中的异常神经元/突触消除，并专门研究 CNDD 将为我提供补体调理素-补体受体相互作用的作用。通过获得 CNDD 核心和财政资源来支持研究，为该项目提供关键支持职业发展和指导工作将确保未来成功获得 NIH R01 在 3 年内过渡到 NDD 领域的既定研究者。