Targeting P2RX7 Signaling as a Biomarker for ADRD

将 P2RX7 信号作为 ADRD 生物标志物

基本信息

批准号：
10739960
负责人：
Jason Stephen Meyer
金额：
$ 22.28万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2023-09-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739960
关键词：
APP-PS1 Acute Adenosine Adult Affect Affinity Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker Amyotrophic Lateral Sclerosis Animal Model Autopsy Benzamides Binding Biodistribution Biological Assay Biological Markers Brain Caspase Cause of Death Cell Death Cell Surface Receptors Cell membrane Cells Central Nervous System Characteristics Chronic Clinical Trials Collaborations Communication Coupled Data Dementia Development Disease Disease Progression Dissociation Effectiveness Encephalitis Environmental Risk Factor Epilepsy Exhibits Exposure to Female Gene Expression Gene Proteins Generations Genetic Genetic Polymorphism Goals Human IL4 gene Image Immune Immune signaling Impaired cognition In Vitro Inflammation Inflammatory Inner mitochondrial membrane Interferon Type II Interleukin-13 Ion Channel Gating Kinetics Ligands Macrophage Membrane Proteins Metabolism Microglia Modeling Molecular Weight Monitor Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Organ Outer Mitochondrial Membrane Oxidative Stress P2X-receptor PET/CT scan Parkinson Disease Penetration Persons Phase Phenotype Play Positron-Emission Tomography Preparation Proteins Public Health Purinoceptor Radiopharmaceuticals Receptor Signaling Reperfusion Injury Research Personnel Risk Role Sensitivity and Specificity Severity of illness Signal Transduction Signaling Molecule Signaling Protein Specificity Testing Therapeutic Time Tracer Traumatic Brain Injury Work antagonist biomarker development cell type cohort dosimetry ecto-nucleotidase extracellular first-in-human imaging agent imaging study improved induced pluripotent stem cell molecular marker mouse model neuroinflammation novel protein complex protein expression radioligand receptor receptor expression recruit response tool treatment response tripolyphosphate

项目摘要

TITLE: Targeting P2RX7 Signaling as a Biomarker for ADRD ABSTRACT Inflammation in the brain has been proposed to be an early predictor for a range of neurodegenerative diseases such as Alzheimer’s disease (AD) and related dementias, Parkinson’s disease, ischemia-reperfusion injury, epilepsy, amyotrophic lateral sclerosis, and traumatic brain injury. Identification and development of biomarkers of neuroinflammation would permit researchers and clinicians to identify “at risk” subjects for these disorders, evaluate severity of disease stage, and effectiveness of possible treatments. Previous work on imaging agents to monitor neuroinflammation has resulted in sub-optimal radiopharmaceuticals that are only correlative in nature. To overcome these limitations, we propose to target the P2X7 receptor (P2X7R) found within the central nervous system and expressed primarily on immune cells. These receptors become activated in neurodegenerative diseases, and are an ideal target to monitor disease progression and therapy response. Previous efforts to develop ligands against this target have been stymied by the presence of P451L mutations that cause dysfunctional P2X7R signaling commonly used animal models. Recent development and characterization of a wild-derived mouse panel showed a high degree of overlap with human neuroinflammation, which is likely due to the retention of functional P2X7R, making them an ideal tool to advance ligands against this receptor. We hypothesize that neuroinflammation is a major initiator of neurodegenerative disease, where P2X7 receptors play a central role; and that developing a novel PET tracer against this receptor will enable phenotypic and therapeutic assessment during aging. Our goal is to characterize the third generation agent (i.e. [18F]GSK1482160) in human cell based assays, and in acute and chronic neuroinflammation models. In Aim 1, we will characterize [18F]-GSK14821604 in vitro in human iPSC derived microglia expressing human P2X7R (hP2X7R) in the APOEE3/E3 or APOEE4/E4 to understand: a) the radioligand depletion conditions for Ki (Aim 1.1); b) binding kinetics for kon, koff, Kd, Bmax (Aim 1.2), and Bp via saturation and association/dissociation kinetics (Aim 1.3). To understand the role of P2X7R in acute and chronic neuroinflammation, in Aim 2, we will use dynamic PET/CT in cross-sectional cohorts of female CAST/EiJ, PWK/PhJ, PWK.APP/PS1 and CAST.APP/PS1 mice. Using dynamic PET/CT we will determine the role of acute (Aim 2.2) and chronic (Aim 2.4) inflammation, where biodistribution (Aim 2.3), thus permitting allometric organ dosimetry for first in human studies. In addition, to validate the sensitivity and specificity of this ligand, (Aim 2.5) dynamic [18F]-GSK1482160 PET/CT at peak P2X7R expression will be conducted, allowing determination of maximum (CAST.APP/PS1) and non-specific (CAST.APP/PS1P2X7R-/-) binding relative to homeostatic levels of microglia (CAST/EiJ). Lastly, to establish test-retest reliability (Aim 2.6) we will repeat imaging in the same subjects separated by 1 week. In all cases, post-mortem brains will undergo Autorad and IHC ex vivo for confirmation. Combined these data will support first in human imaging studies in collaboration with the ADNI.

标题：将 P2RX7 信号作为 ADRD 生物标志物抽象的大脑炎症被认为是一系列神经退行性疾病的早期预测因素例如阿尔茨海默病（AD）和相关痴呆症、帕金森病、缺血再灌注损伤、癫痫、肌萎缩侧索硬化症和创伤性脑损伤的生物标志物的鉴定和开发。神经炎症的研究将使研究人员和指挥官能够识别出患有这些疾病的“危险”对象，评估疾病阶段的严重程度以及可能的治疗方法的有效性。监测神经炎症导致了次优的放射性药物，这些药物仅与为了克服这些限制，我们建议以中枢内发现的 P2X7 受体 (P2X7R) 为目标。神经系统并主要在免疫细胞上表达这些受体被激活。神经退行性疾病，是监测疾病进展和治疗反应的理想目标。之前开发针对该靶点的配体已因 P451L 突变的存在而受阻导致 P2X7R 信号传导功能障碍的常用动物模型。野生小鼠组的特征显示与人类神经炎症高度重叠，这可能是由于功能性 P2X7R 的保留，使它们成为推进配体对抗的理想工具我们发现神经炎症是神经退行性疾病的主要引发因素，其中 P2X7 受体发挥核心作用；开发针对该受体的新型 PET 示踪剂将使衰老过程中的表型和治疗评估成为可能。我们的目标是描述第三个特征。人类细胞分析中以及急性和慢性中的生成剂（即[18F]GSK1482160）在目标 1 中，我们将在体外对人 iPSC 衍生的 [18F]-GSK14821604 进行表征。在 APOEE3/E3 或 APOEE4/E4 中表达人 P2X7R (hP2X7R) 的小胶质细胞了解：a) 放射性配体 Ki（目标 1.1）的耗尽条件；b）通过饱和度和 kon、koff、Kd、Bmax（目标 1.2）和 Bp 的结合动力学结合/解离动力学（目标 1.3）了解 P2X7R 在急性和慢性中的作用。神经炎症，在目标 2 中，我们将在女性 CAST/EiJ 的横断面队列中使用动态 PET/CT，使用动态 PET/CT，我们将确定 PWK/PhJ、PWK.APP/PS1 和 CAST.APP/PS1 小鼠的急性作用。（目标 2.2）和慢性（目标 2.4）炎症，其中生物分布（目标 2.3），从而允许异速器官此外，还验证了该配体的敏感性和特异性（目标 2.5）。将在 P2X7R 表达峰值时进行动态 [18F]-GSK1482160 PET/CT，从而确定相对于稳态水平的最大 (CAST.APP/PS1) 和非特异性 (CAST.APP/PS1P2X7R-/-) 结合最后，为了建立重测可靠性（目标 2.6），我们将在同一过程中重复成像。在所有情况下，死后大脑将在体外进行 Autorad 和 IHC。综合这些数据将支持与 ADNI 合作进行的人类成像研究。