Development of PET imaging probes for ROCK2

ROCK2 PET 成像探针的开发

基本信息

批准号：
10359030
负责人：
Zhengxin Cai
金额：
$ 82.65万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359030
关键词：
APP-PS1 Affect Affinity Age Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid beta-Protein Anatomy Autopsy Binding Biological Assay Biological Markers Brain Characteristics Chemicals Clinical Research Clinical Trials Cognition Cyclic AMP-Dependent Protein Kinases Data Dementia Development Diagnosis Disease Disease Progression Dose Drug Kinetics Early Diagnosis Early Intervention Economic Burden Emotional Family Future Genetic Heart Diseases Hippocampus (Brain)Human Hydrogen Bonding Image Image Analysis In Vitro J20 mouse Kinetics Label Lead Libraries Ligands Literature Malignant Neoplasms Mediating Metabolism Methods Modeling Molecular Weight Monitor Mus Neurodegenerative Disorders Pathologic Pathway interactions Patients Penetration Persons Pharmaceutical Preparations Plasma Positron-Emission Tomography Preparation Process Property Protein Kinase Proteins ROCK1 gene Radiolabeled Rodent Rodent Model Senile Plaques Signal Pathway Societies Specificity Structure Synapses Testing Time Toxic effect Tracer Transgenic Organisms Translating United States Up-Regulation Validation Western Blotting asymptomatic Alzheimer&apos s disease base blood-brain barrier penetration brain tissue cheminformatics clinical investigation cognitive function density design dosimetry early detection biomarkers effective intervention familial Alzheimer disease frontal lobe human study imaging modality imaging probe imaging study improved in vivo inhibitor longitudinal positron emission tomography neuroimaging new therapeutic target nonhuman primate novel overexpression pharmacokinetic model pre-clinical prevent prodromal Alzheimer&apos s disease public health relevance radiotracer response rho socioeconomics tau aggregation translation to humans treatment strategy white matter

项目摘要

ABSTRACT The objective of this project is to develop, validate, and translate novel positron emission tomography (PET) imaging probes for rho-associated coiled-coil containing protein kinase 2 (ROCK2). Consistent with prior postmortem studies, significant synaptic loss was found using SV2A PET in the hippocampus and frontal cortex of patients with MCI and early AD, indicating progressive synaptic loss along the disease path. The synapse loss in MCI/AD patients is expected to be mediated through activation of rho/ROCK2 signaling pathway. Elevated ROCK2 has been observed in postmortem brain tissues of asymptomatic AD and MCI patients and in transgenic rodent models of familial AD. These data demonstrate the potential of detecting preclinical and prodromal AD through ROCK2 PET imaging, which may lead to identification of new therapeutic targets with a defined early intervention time window to delay or prevent the synapse loss and onset of dementia. Therefore, we propose to develop and translate ROCK2 PET imaging probes for future clinical investigations. Successful completion of this project will yield a ROCK2 PET imaging probe ready to be tested in humans as a sensitive and quantitative in vivo biomarker for preclinical and prodromal AD, which will allow early interventions to slow or halt disease progression.

抽象的该项目的目的是开发，验证和翻译新型正电子发射断层扫描（PET）与Rho相关的包含蛋白激酶2（Rock2）的Rho相关盘圈的成像探针。与先验一致验尸研究，在海马和额叶中使用SV2A PET发现了明显的突触损失 MCI和AD早期患者的皮质，表明沿疾病路径进行性突触丧失。这预计MCI/AD患者的突触损失将通过激活Rho/Rock2信号传导介导路径。在无症状AD和MCI的死后脑组织中观察到了升高的岩石2 患者和家族性AD的转基因啮齿动物模型。这些数据证明了检测的潜力通过Rock2 PET成像通过临床前和前驱AD，这可能导致新的鉴定具有定义的早期干预时间窗口的治疗目标，以延迟或防止突触损失和痴呆症的发作。因此，我们建议开发和翻译Rock2 PET成像探针以未来临床研究。该项目的成功完成将产生Rock2 PET成像探测器准备在人类中作为一种敏感和定量的体内生物标志物进行测试这将使早期干预措施减慢或停止疾病的进展。