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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病（AD）是一种神经退行性疾病，也是老年人和老年人痴呆的主要原因。目前尚无治愈方法，坏死性凋亡是一种复杂且受调节的半胱天冬酶依赖性细胞死亡。由多种蛋白质成员介导的机制，例如受体相互作用蛋白激酶 1（RIP1 或 RIPK1）值得注意的是，RIPK1 被人类 AD 大脑中的小胶质细胞上调，并介导炎症。 AD 中与疾病相关的小胶质细胞反应。不幸的是，没有合适的非侵入性神经影像工具来研究动物的这些过程体内可视化 RIPK1 的生物标志物的开发代表了理解的关键一步。此外，这些技术将加速 RIPK1 在大脑中的正常功能和病理生理学。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用于啮齿动物和非人类 RIPK1 成像的新型 PET 成像探针在 R61 阶段对灵长类动物进行研究，并在 R33 阶段进行首次人体成像，取得了成功。本次资助期间的对照成像将导致对患者进行进一步的成像研究。