权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结