The inflammatory mechanisms underlying olfactory dysfunction in prognosis of TBI progression to dementia

嗅觉功能障碍的炎症机制在 TBI 进展为痴呆的预后中的作用

基本信息

批准号：
10447477
负责人：
Shaolin Liu
金额：
$ 64.47万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447477
关键词：
Ablation Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Anosmia Atrophic Behavior Biochemical Cells Chronic Clinical Clinical Research Cognitive Cognitive deficits Data Dementia Development Diagnosis Disease Management Disease Progression Early Diagnosis Electrophysiology (science)Exhibits Functional disorder Future Generations Genetic Hippocampus (Brain)Impairment In Vitro Incidence Inflammation Inflammatory Inflammatory Response Injury Ion Channel Knockout Mice Light Link Literature Mediating Medical Microglia Microscopy Modeling Molecular Mus NADPH Oxidase Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurologic Neurons Olfactory Pathways Olfactory dysfunction Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Pharmacology Population Positioning Attribute Prevention Prognosis Quality of life Reactive Oxygen Species Recording of previous events Research Risk Risk Factors Role Sensory Disorders Severity of illness Signal Transduction Structure Survivors Symptoms Synapses Therapeutic Therapeutic Effect Trauma Traumatic Brain Injury accurate diagnosis base behavioral impairment controlled cortical impact cytokine designer receptors exclusively activated by designer drugs early detection biomarkers effective therapy epidemiology study experimental study functional outcomes hyperphosphorylated tau improved in vivo inhibitor interdisciplinary approach network dysfunction neurobehavioral test neuroinflammation neuronal excitability neuropsychiatry neurotoxic olfactory bulb operation piriform cortex prodromal Alzheimer&apos s disease synaptic function tau-1 treatment strategy

项目摘要

Project Summary 20–68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can compromise not only the quality of life but also cognitive and neuropsychiatric functions. Although post- traumatic anosmia has been documented in the medical literature for more than a century, neither the underlying mechanisms nor treatment remain clear. Moreover, the occurrence of TBI significantly increases risk for the development of Alzheimer’s disease (AD) or non-AD forms of dementia. Recent studies of OD have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Thus, TBI survivors with OD may be an early sign heralding its progression to dementia. AD pathogenesis revealed that the peripheral olfactory pathways including the olfactory bulb (OB) are the potential structural candidates responsible for OD in prodromal AD. Emerging studies have associated OD with the presence of OB inflammatory response, suggesting that OB pathology may provide a mechanistic link between TBI and AD or dementia. Recent data indicate that TBI-induced rapid and persistent pro-inflammatory responses in the OB were accompanied by increased phosphorylated tau and OB atrophy, resulting in early and persistent olfactory deficits. New data indicate that microglia-mediated inflammation contributed to neuronal hyperexcitation in the OB which was mitigated in the absence of Hv1, a newly discovered microglial ion channel required for NADPH oxidase-dependent generation of reactive oxygen species. Based on these findings and our preliminary data, we hypothesize that early after TBI microglial Hv1-mediated inflammation in the OB contributes to hyperexcitation of local neurons leading to olfactory dysfunction, thus heralding its progression to late-onset neurodegeneration. With multidisciplinary approaches including the Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic inhibition of OB microglia, microglia-specific and inducible Hv1 KO mice combined with microscopy and biochemical approaches, and comprehensive neurobehavioral testing, we will examine neuroinflammation and neurodegeneration in the OB in a well-established controlled cortical impact mouse TBI model and their correlation with OD and late-onset dementia-like behaviors (AIM 1). Furthermore, powerful in vivo and in vitro electrophysiological approaches will be applied to characterize detrimental effects of TBI-induced inflammation on network and synaptic functions in the OB (AIM 2). Lastly, we will determine whether genetic or pharmacological inhibition of inflammatory pathways in the OB through intranasal delivery mitigates TBI-induced inflammation and neurodegeneration thus improves functional outcomes (AIM 3). Our study will be the first to link olfactory dysfunction to dementia and neurodegeneration following TBI. Our findings will potentially shed light on developing effective approaches for early and accurate diagnosis of TBI-associated OD in the development of neurodegeneration and dementia.

项目摘要 20–68％的创伤性脑损伤（TBI）患者暴露于创伤相关的嗅觉定义（OD）可以不仅妥协了生活质量，还妥协了认知和神经精神病的功能。虽然创伤性厌氧在医学文献中已经记录了一个多世纪，既没有基本机制和治疗方法仍然很清楚。此外，TBI的出现显着增加阿尔茨海默氏病（AD）或非AD形式的痴呆形式的风险。最近关于OD的研究将其作为早期生物标志物的潜力以诊断神经退行性疾病及其疾病的潜力进展。那就是，具有OD的TBI生存可能是一个早期的迹象，使其发展为痴呆症。广告发病机理表明，包括嗅球在内的周围嗅觉途径（OB）是潜力结构性候选者负责前驱AD中的OD。新兴研究与OD有关 OB炎症反应的存在，表明OB病理可能会提供机械联系 TBI和AD或痴呆症。最近的数据表明，TBI引起了快速和持久的促炎通过增加磷酸化的tau和ob萎缩来实现OB中的反应，从而早期持续的嗅觉定义。新数据表明小胶质细胞介导的炎症有助于在没有HV1的情况下，OB中的神经元过度刺激是一种新发现的小胶质细胞 NADPH氧化物依赖性产生活性氧所需的离子通道。基于这些调查结果和我们的初步数据，我们假设TBI小胶质细胞HV1介导的炎症之后的早期 OB会导致局部神经元过度刺激导致嗅觉功能障碍，从而预示其发展为晚期神经退行性变化。采用多学科方法，包括设计师专门激活的设计师受体基于药物（Dreadd）的化学剂抑制OB小胶质细胞，小胶质细胞特异性和诱导HV1 KO 小鼠结合了显微镜和生化方法以及全面的神经行为测试，我们将检查OB中的神经炎症和神经变性。影响小鼠TBI模型及其与OD和晚发性痴呆行为的相关性（AIM 1）。此外，将采用强大的体内和体外电生理方法来表征 TBI诱导的感染对OB中网络和突触功能的有害影响（AIM 2）。最后，我们将通过鼻内递送减轻TBI诱导的感染和神经变性可改善功能结果（目标3）。我们的研究将是第一个将嗅觉功能障碍与TBI之后的神经退行性联系在一起的研究。我们的发现可能会阐明开发有效方法以早期和准确的诊断 TBI相关的OD在神经变性和痴呆的发展中。