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：
10645083
负责人：
Shaolin Liu
金额：
$ 63.11万
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/10645083
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 Early identification Electrophysiology (science)Exhibits Functional disorder Future Generations Genetic Hippocampus Impairment In Vitro Incidence Infiltration Inflammation Inflammatory Inflammatory Response Injury Ion Channel Knockout Mice 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 Peripheral 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 TBI Patients Therapeutic Therapeutic Effect Trauma Traumatic Brain Injury accurate diagnosis behavioral impairment controlled cortical impact cytokine designer receptors exclusively activated by designer drugs early detection biomarkers effective therapy epidemiology study experimental study functional improvement functional outcomes glial activation hyperphosphorylated tau in vivo inhibitor interdisciplinary approach network dysfunction neurobehavioral test neuroinflammation neuronal excitability neuropathology neuropsychiatry neurotoxic olfactory bulb operation pharmacologic 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.

项目概要 20-68% 的创伤性脑损伤 (TBI) 患者表现出与创伤相关的嗅觉缺陷 (OD)，这可能会导致不仅影响生活质量，而且影响认知和神经精神功能。一个多世纪以来，医学文献中已有创伤性嗅觉丧失的记载，但无论是此外，TBI 的发生率显着增加。最近对 OD 的研究发现，存在罹患阿尔茨海默病 (AD) 或非 AD 形式的痴呆症的风险。重点关注其作为诊断神经退行性疾病及其疾病的早期生物标志物的潜力因此，患有 OD 的 TBI 幸存者可能是预示其进展为痴呆的早期征兆。发病机制揭示了包括嗅球（OB）在内的外周嗅觉通路是潜在的新兴研究中导致 OD 的结构候选者将 OD 与 OD 相关联。 OB 炎症反应的存在，表明 OB 病理学可能提供了 OB 之间的机制联系 TBI 和 AD 或痴呆症最近的数据表明 TBI 诱导的快速且持续的促炎症。 OB 中的反应伴随着磷酸化 tau 蛋白的增加和 OB 萎缩，导致早期新数据表明小胶质细胞介导的炎症导致了这种情况。 OB 中的神经元过度兴奋在缺乏 Hv1（一种新发现的小胶质细胞）的情况下得到缓解 NADPH 氧化酶依赖性活性氧生成所需的离子通道基于这些。和我们的初步数据相比，我们在 TBI 后早期就发现小胶质细胞 Hv1 介导的炎症 OB 导致局部神经元过度兴奋，导致嗅觉功能障碍，从而预示着其迟发性神经变性进展。采用多学科方法，包括由设计师独家激活的设计师受体基于药物 (DREADD) 的 OB 小胶质细胞、小胶质细胞特异性和诱导型 Hv1 KO 的化学遗传学抑制小鼠结合显微镜和生化方法以及全面的神经行为测试，我们将在完善的受控皮质中检查 OB 中的神经炎症和神经变性影响小鼠 TBI 模型及其与 OD 和晚发性痴呆样行为的相关性 (AIM 1)。此外，将应用强大的体内和体外电生理学方法来表征 TBI 引起的炎症对 OB 网络和突触功能的痛苦影响 (AIM 2)。我们将确定 OB 中炎症途径的遗传或药物抑制是否通过鼻内给药可减轻 TBI 引起的炎症和神经退行性变，从而改善功能结果（目标 3）。我们的研究将首次将嗅觉功能障碍与创伤性脑损伤后的痴呆和神经退行性疾病联系起来。我们的研究结果可能有助于开发有效的方法来进行早期和准确的诊断 TBI 相关的 OD 在神经退行性变和痴呆的发展中。