Investigating whole-body innate immune activation in Alzheimer's disease using PET imaging and immune profiling

使用 PET 成像和免疫分析研究阿尔茨海默病的全身先天免疫激活

基本信息

批准号：
10749393
负责人：
Aisling Chaney
金额：
$ 24.77万
依托单位：
WASHINGTON UNIVERSITY
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：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749393
关键词：
AD transgenic mice Address Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Astrocytes Autopsy Biological Markers Blood Blood Platelets Bone Marrow Brain Cells Central Nervous System Clinical Clinical assessments Complex Data Development Diabetes Mellitus Diagnosis Disease Disease Progression Endothelial Cells Environment Faculty Funding Genes Goals Gold Heart Diseases Human Image Immune Immune Targeting Immune response Immunology Impaired cognition Infection Infiltration Inflammation Inflammatory Inflammatory Response Innate Immune Response Investigation Knowledge Link Macrophage Magnetic Resonance Imaging Measures Mentors Methods Microglia Monitor Multiple Sclerosis Mus Myeloid Cells Nerve Degeneration Neuroimmune Neurosciences Obesity Outcome Pathogenesis Patients Peripheral Peripheral Nervous System Phase Phenotype Play Positron-Emission Tomography Proteins Protocols documentation Radiology Specialty Reporting Research Personnel Resources Risk Role Severity of illness Specificity Spleen Techniques Therapeutic Time Tissues Tracer Training Viral Work brain tissue clinical application cohort comorbidity genome wide association study immune activation immune function immune modulating agents immunological status immunoregulation improved in vivo innovation insight interest lymph nodes member mild cognitive impairment molecular imaging mouse model multidisciplinary nervous system disorder neuroinflammation novel patient population pre-clinical receptor response screening skills spatiotemporal specific biomarkers stroke model systemic inflammatory response tenure track therapeutically effective tool treatment strategy uptake

项目摘要

Project Summary/Abstract The emerging role of inflammation in the pathogenesis of Alzheimer’s disease (AD) is shifting how the field is approaching its treatment, with growing interest in the development of immunomodulatory therapeutics. The appropriate therapeutic window and patient population for such treatment strategies remains to be determined. Importantly, current understanding of inflammation in AD has largely arose from brain tissues studied in isolation. However, it has become clear that peripheral inflammatory responses may influence both AD risk and disease progression. Here, I propose to use whole-body positron emission tomography (PET) of the translocator protein 18kDa (TSPO) and triggering receptor on myeloid cells 1 (TREM1) and complementary immune profiling techniques to non-invasively assess peripheral and central inflammation in Alzheimer’s disease. This project aims to use parallel preclinical (Aim 1) and clinical approaches (Aims 2 & 3) to increase the fundamental understanding of inflammation in disease while actively improving clinical assessment. Our specific aims are (1) to characterize distinct peripheral and central myeloid cell responses and investigate the effects of systemic inflammation on neuroinflammation in the 5XFAD mouse model of AD; (2) to develop a clinically feasible approach to quantify whole-body TSPO-PET uptake in AD patients; and (3) to study whole-body immune signatures associated with disease severity in AD and mild cognitive impairment patients using whole-body TSPO-PET and blood-based immune profiling. The innovation of this work lies in the whole-body approach for the investigation of inflammation in AD, which has yet to be investigated. TREM1-PET is the first tool to specifically image proinflammatory peripheral myeloid cells in vivo. Preclinical investigation using TREM1-PET and clinical application of whole-body TSPO-PET imaging in patients will provide novel insights into the complex neuroimmune interactions involved in AD pathogenesis. The significance of this work is that enhanced understanding of whole-body innate immune responses in AD has the potential to not only improve diagnosis and disease monitoring, but also to develop and screen for effective disease modifying therapeutics. Additionally, these methods can be applied to impact our understanding of inflammation across a broad range of inflammatory and neurological disorders.

项目概要/摘要炎症在阿尔茨海默病 (AD) 发病机制中的新作用正在改变该领域的研究方式接近其治疗，人们对免疫调节疗法的开发越来越感兴趣。这种治疗策略的适当治疗窗口和患者群体仍有待确定。重要的是，目前对 AD 炎症的理解很大程度上来自于单独研究的脑组织。然而，很明显，外周炎症反应可能会影响 AD 风险和疾病在这里，我建议使用易位蛋白的全身正电子发射断层扫描（PET） 18kDa (TSPO) 和骨髓细胞触发受体 1 (TREM1) 以及互补免疫分析非侵入性评估阿尔茨海默病的外周和中枢炎症的技术。该项目旨在使用并行的临床前（目标 1）和临床方法（目标 2 和 3）来提高对疾病炎症的基本了解，同时积极改进我们的具体临床评估。目的是 (1) 表征不同的外周和中枢骨髓细胞反应并研究 5XFAD 小鼠 AD 模型中炎症对神经炎症的影响 (2) 开发临床模型量化 AD 患者全身 TSPO-PET 摄取的可行方法；以及 (3) 研究全身免疫；使用全身与 AD 和轻度认知障碍患者的疾病严重程度相关的特征 TSPO-PET 和血液免疫分析。这项工作的创新之处在于研究 AD 炎症的全身方法， TREM1-PET 是第一个专门对促炎性外周骨髓细胞进行成像的工具。使用 TREM1-PET 的临床前研究和全身 TSPO-PET 的临床应用。患者成像将为 AD 中复杂的神经免疫相互作用提供新的见解这项工作的意义在于增强了对全身先天免疫的认识。 AD 的反应不仅有可能改善诊断和疾病监测，而且有可能发展和此外，这些方法可用于影响我们的疾病。了解各种炎症和神经系统疾病的炎症。