Molecular imaging of RIPK1/necroptosis as a key biomarker in Alzheimer's disease

RIPK1/坏死性凋亡作为阿尔茨海默病关键生物标志物的分子成像

• 批准号: 10378615
• 负责人: Changning Wang
• 金额: $ 83.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378615
• 关键词: AD transgenic mice; APP-PS1; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animals; Attenuated; Autopsy; Binding; Biological Assay; Biological Markers; Brain; Brain imaging; Brain region; Caspase; Cell Death; Cell model; Clinical Research; Clinical Trials; Complex; Data; Data Analyses; Dementia; Development; Disease; Disease Progression; Dose; Drug Kinetics; Elderly; FDA approved; Functional disorder; Genetic; Goals; Grant; Hippocampus (Brain); Human; Image; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Ligands; Measures; Mediating; Medicine; Memory impairment; Metabolism; Methods; Microglia; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurology; Neurons; Pathogenesis; Pathologic Processes; Pathology; Patient Selection; Patients; Performance; Phagocytes; Pharmacology; Phase; Phenotype; Plasma; Positron-Emission Tomography; Process; Property; Protein Kinase; Proteins; RIPK1 gene; Radioactivity; Radiolabeled; Receptor Down-Regulation; Reporting; Research; Rodent; Senile Plaques; Specificity; Techniques; Testing; Therapeutic; Tracer; Transgenic Mice; Translating; Translational Research; abeta accumulation; amyloid pathology; base; design; dosimetry; drug development; experience; experimental study; first-in-human; human disease; human imaging; human old age (65+); imaging agent; imaging biomarker; imaging probe; imaging study; improved; in vivo; in vivo imaging; inhibitor; kinetic model; man; member; molecular imaging; mouse model; multidisciplinary; neuroimaging; nonhuman primate; novel; novel marker; radiochemical; radiotracer; recruit; response; small molecule therapeutics; success; tau Proteins; tau aggregation; tau phosphorylation; tau-1; therapeutic target; tool; uptake

Project Summary Alzheimer’s disease (AD) is a neurodegenerative disorder and the primary cause of dementia in the elderly and there is no cure currently available. Necroptosis is a complex and regulated caspase-independent cell death mechanism mediated by various protein members, e.g. receptor-interacting protein kinase 1 (RIP1 or RIPK1) involving inflammation. Notably, RIPK1 is up-regulated by microglial cells in human AD brains and mediates a disease-associated microglial response in AD. Unfortunately, there are no suitable non-invasive neuroimaging tools for investigating these processes in animals or in man. The development of a biomarker for visualizing RIPK1 in vivo represents a key step in understanding both the normal function and pathophysiology of RIPK1 in brain. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with RIPK1. The project is designed to validate a novel PET imaging probe for RIPK1 imaging in rodents and non-human primates during the R61 phase and perform the first-in-human imaging in the R33 phase. The success of healthy control imaging in this grant period will lead to further imaging study in patients.

项目摘要 阿尔茨海默病(AD)是一种神经退行性疾病，是老年人和老年人痴呆的主要原因 目前还没有治愈方法。坏死性下垂是一种复杂的、受调控的caspase非依赖性细胞死亡。 多种蛋白质成员的调节机制，如受体相互作用蛋白激酶1(RIP1或RIPK1) 涉及炎症的。值得注意的是，RIPK1被人类AD脑中的小胶质细胞上调，并介导了一种 阿尔茨海默病相关的小胶质细胞反应。 不幸的是，还没有合适的非侵入性神经成像工具来研究动物的这些过程。 或者在人类身上。在体内观察RIPK1的生物标志物的开发是理解RIPK1的关键一步 RIPK1在脑内的正常功能和病理生理。此外，这些技术将加速 发现选择性与RIPK1相互作用的小分子疗法。 该项目旨在验证一种新型的PET成像探针，用于在啮齿动物和非人类中进行RIPK1成像 在R61阶段的灵长类动物，并在R33阶段进行第一次人类成像。健康的成功 在此授权期内的对照成像将导致在患者中进行进一步的成像研究。