Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease

用于阿尔茨海默病转化研究的 Sigma-1 受体放射性配体

• 批准号: 10670485
• 负责人: YIYUN HENRY HUANG
• 金额: $ 83.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670485
• 关键词: Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Disease Models; Animal Diseases; Applications Grants; Autoradiography; Binding; Biochemical; Bioenergetics; Biological Markers; Brain; Calcium; Calcium Signaling; Cells; Cessation of life; Cholesterol Homeostasis; Clinical; Clinical Trials; Complex; Coupled; Data; Degenerative Disorder; Dementia; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Early Diagnosis; Endoplasmic Reticulum; Equilibrium; Etiology; Evaluation; Functional disorder; Generations; Genetic Polymorphism; Human; Huntington Disease; ITPR1 gene; Image; Immune response; Immunoglobulin binding proteins; Inositol; Investigation; Kinetics; Label; Ligands; Link; Measurement; Mediating; Membrane; Mental Depression; Mental disorders; Methods; Mitochondria; Molecular; Molecular Chaperones; Monitor; Monkeys; Morphology; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Oral; Organ; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Persons; Pharmacology; Play; Positron-Emission Tomography; Procedures; Production; Proteins; Protocols documentation; Reaction; Receptor Gene; Regulation; Reproducibility; Research; Risk Factors; Role; Safety; Scanning; Schizophrenia; Signal Transduction; Skeleton; Slice; Specificity; Surrogate Markers; Synapses; Synaptic Vesicles; Testing; Toxic effect; Translational Research; Translations; Treatment outcome; Work; apolipoprotein E-4; calcium metabolism; cholinergic; cognitive function; density; disease mechanisms study; donepezil; dosimetry; drug candidate; early detection biomarkers; enantiomer; experience; experimental study; first-in-human; glucose-regulated proteins; healthy volunteer; human study; human subject; hyperphosphorylated tau; imaging agent; in vivo; insight; lipid metabolism; mild cognitive impairment; mitochondrial dysfunction; mouse model; nervous system disorder; neuropsychiatric disorder; nonhuman primate; novel; pre-clinical; radiochemical; radioligand; receptor; relating to nervous system; sigma-1 receptor; tau Proteins; therapeutic development; therapeutic target; tool; whole body imaging

In this grant application we propose to develop and validate an optimal 18F-labeled sigma-1 (σ1) receptor radioligand for translational research in Alzheimer’s disease (AD) to further elucidate the role of σ1 receptor in AD pathogenesis and progression, to probe longitudinal changes in σ1 receptor in AD animal models, along with the synapse biomarker synaptic vesicle protein 2A (SV2A), and AD pathologic biomarkers b-amyloid (Ab) and tau, and to explore the potential of σ1 receptor imaging for early diagnosis of AD. AD is a progressive degenerative disorder that afflicts 6 million people in the USA. From a diagnostic perspective, AD is increasingly viewed along a continuum from preclinical AD, to mild cognitive impairment (MCI), and to AD-dementia. The clinical dementia of AD is coupled to a distinct pathology, with plaques composed of b-amyloid (Ab), neurofibrillary tangles of hyperphosphorylated tau protein, and synaptic loss. However, the molecular mechanism(s) of AD pathogenesis is complex and remains elusive. Several hypotheses have been put forward, including the b-amyloid hypothesis, the misfolded tau protein hypothesis, the cholinergic hypothesis, and the involvement of oxidative stress and calcium dyshomeostasis. Before the accumulation of plaques and tangles, the biochemical and morphological changes, such as altered calcium, cholesterol, and lipid metabolism, altered mitochondrial dynamics, and reduced bioenergetic interaction, are all closely associated with functions localized to the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). The σ1 receptor is situated at the MAM. The most recent research has located the earliest Ab generation in AD to neurons in the MAM, and its critical regulation by the σ1 receptor, thereby confirming the central role of σ1 receptor in AD pathogenesis. As such the σ1 receptor is considered an important target for AD therapeutic development. As a surrogate marker for mitochondria function and regulator of Ab production on the MAM, it also holds great promise as a biomarker for diagnosis of AD at its earliest stage. The research proposed in this application will bridge an important gap in the understanding of the σ1 receptor in AD pathogenesis and progression by leveraging the unique expertise and experience at Yale in novel PET radioligand development, AD mechanism study, and therapeutic target identification. Investigation of the σ1 receptor in AD animal models longitudinally in relation to biomarkers for synaptic density, Ab, and tau, is a natural extension of our ongoing research. When carried to completion, this project will provide further insights into the etiology of AD, and help identify a most sensitive and effective biomarker for early AD diagnosis, and for monitoring of disease progression and the efficacy of emerging AD therapies.

在此赠款应用程序中，我们建议开发和验证最佳的18F标记Sigma-1（σ1）接收器 用于翻译阿尔茨海默氏病（AD）研究的放射性基因，以进一步阐明σ1受体在 AD发病机理和进展，以探测AD动物模型中σ1受体的纵向变化， 突触生物标志物合成囊泡蛋白2a​​（SV2A）和AD病理生物标志物B-淀粉样蛋白（AB）和 tau，并探索σ1受体成像的潜力，以便早期诊断AD。 AD是一种渐进的退化性疾病，在美国遭受了600万人的困扰。来自诊断 透视图，越来越多地沿着从临床前广告到轻度认知障碍（MCI）的连续观察。 和addementia。 AD的临床痴呆症与由斑块耦合到不同的病理学，由 B-淀粉样蛋白（AB），高磷酸化tau蛋白的神经纤维缠结和突触损失。但是， AD发病机理的分子机制是复杂的，并且仍然难以捉摸。几个假设已经 提出，包括B-淀粉样假说，错误折叠的TAU蛋白假说，胆碱能假设， 以及氧化应激和钙异质症的参与。在斑块积累之前 缠结，生化和形态学变化，例如钙，胆固醇和脂质代谢的改变， 线粒体动力学的改变和降低的生物能相互作用都与功能紧密相关 定位于线粒体相关的内质网（ER）膜（MAMS）。 σ1受体是 位于妈妈。最新的研究已将广告中最早的AB一代定位到了神经元中 MAM及其对σ1受体的临界调节，从而确认了σ1受体在AD中的中心作用 发病。因此，σ1受体被认为是AD治疗发育的重要目标。作为 线粒体功能的替代标记和MAM上AB生产的调节剂，它也很棒 在最早的阶段作为诊断AD的生物标志物的承诺。 本应用程序中提出的研究将弥合理解σ1接收器的重要差距 通过利用新颖宠物的耶鲁大学独特的专业知识和经验，在AD发病机理和发展中 放射线发展，AD机理研究和治疗靶标识别。 σ1的研究 AD动物模型中的受体与突触密度的生物标志物相关，AB和TAU是自然的 扩展我们正在进行的研究。完成完成后，该项目将提供进一步的见解 AD的病因，并帮助确定早期AD诊断的最敏感和有效的生物标志物，以及 监测疾病进展和新兴广告疗法的有效性。