Investigation of molecular changes in mGluR5 and SV2A to study synaptic alterations in Alzheimer's disease using PET.

项目总结/摘要 该提案旨在扩大对阿尔茨海默病（AD）病理生理学的理解， 通过确保及时/准确的诊断以及有效地预防和治疗， 治疗AD。在美国，AD困扰着超过500万人，并且目前没有任何疗法改变AD的病程。 正电子发射断层扫描（PET）成像已成功地用于调查生活中的变化 人类在分子水平上，帮助诊断和了解AD。因此， AD可以用多示踪剂神经成像和神经心理学表征在体内研究。 突触水平的分子变化与AD相关。代谢型谷氨酸受体 亚型5（mGluR 5）存在于整个皮层的突触中，并且是淀粉样蛋白β诱导的AD的介导剂 病理因此，mGluR 5是AD的候选生物标志物和治疗干预的靶点， 使其在AD中的检测成为一个重要目标。此外，突触囊泡糖蛋白2A（SV 2A）是一种前 突触蛋白具有作为突触密度的第一体内标记物的潜力。由于突触丢失在 在AD的最早阶段，SV 2A结合是疾病进展的可靠标志。 这项提案的长期目标是应用PET方法来了解神经生物学 使用[18 F]FPEB（mGluR 5的特异性配体）和[11 C]UCB-J（mGluR 5的特异性配体）与AD相关的变化 SV 2A（突触密度）。这可能通过以下方式产生显著影响：（i）确定mGluR 5 受体的可用性，发生在AD（目的1），（ii）确定突触密度的变化， 在AD期间可检测（目的2），和（iii）了解mGluR 5受体变化之间的关系 可用性和突触密度（目标3）。这些调查将为AD提供有价值的了解 疾病过程，并导致新的治疗和治疗生物标志物的发展。 拟议中的计划将整合耶鲁大学医学院最先进的生物医学成像设施， 医学与耶鲁大学阿尔茨海默病研究中心的强大资源。导师团队 由AD诊断和治疗、人体PET成像领域的国际知名专家组成， 生物统计学该计划将提供候选人的技能和经验，成为一个独立的 AD神经生物学和PET成像领域的研究者。具体的培训目标包括：（一）发展 在人类AD和PET研究的行为先进的技能，（ii）发展计算和 PET示踪剂动力学建模和图像分析的统计方法，和（iii）开发一个独立的 AD分子神经成像计划，所有这些都是为了最终维持独立资助的研究事业。 职业发展奖提供结构化的机会，旨在发展创新领域的专业知识。 神经生物学研究方法和职业生涯作为一个独立的AD和认知障碍调查。

PROJECT SUMMARY/ABSTRACT This proposal seeks to expand the understanding of Alzheimer’s disease (AD) pathophysiology with the ultimate goals of enhancing care by ensuring timely/accurate diagnosis, as well as preventing and effectively treating AD. AD afflicts over 5 million people in the US and no current therapy modifies the course of AD. Positron Emission Tomography (PET) imaging has been successfully employed to investigate changes in living humans at the molecular level, aiding in the diagnosis and understanding of AD. Therefore, the neurobiology of AD can be studied in vivo with multi-tracer neuroimaging and neuropsychological characterization. Molecular changes at the synaptic level are associated with AD. Metabotropic glutamate receptor subtype 5 (mGluR5) is present at synapses throughout the cortex and is a mediator of amyloid β induced AD pathology. Therefore, mGluR5 is a candidate biomarker for AD and a target for therapeutic intervention, making its detection in AD an important goal. Furthermore, synaptic vesicle glycoprotein 2A (SV2A) is a pre- synaptic protein with potential as the first in vivo marker of synaptic density. Since synaptic loss is observed in the earliest stages of AD, SV2A binding stands to be a robust marker of disease progression. The long-term objective of this proposal is to apply PET methods to understand the neurobiological changes associated with AD using [18F]FPEB, a specific ligand for mGluR5, and [11C]UCB-J, a specific ligand for SV2A (synaptic density). This is likely to have a significant impact by (i) determining the changes in mGluR5 receptor availability that occur during AD (Aim 1), (ii) determining the changes in synaptic density that are detectible during AD (Aim 2), and (iii) understanding the relationship between changes in mGluR5 receptor availability and synaptic density (Aim 3). These investigations will provide valuable understanding of the AD disease process and lead to the development of both novel treatments and therapeutic biomarkers. The proposed program will integrate state-of-the-art biomedical imaging facilities at the Yale School of Medicine with the robust resources of the Yale Alzheimer’s Disease Research Center. The mentorship team consists of internationally renowned experts in AD diagnostics and therapeutics, human PET imaging, and biostatistics. The program will provide the candidate with the skills and experience to become an independent investigator in the fields of AD neurobiology and PET imaging. Specific training goals include: (i) developing advanced skills in the conduct of human AD and PET research, (ii) developing expertise in computational and statistical methods for PET tracer kinetic modeling and image analysis, and (iii) developing an independent program of AD molecular neuroimaging, all in order to ultimately sustain an independently funded research career. The career development award proposes structured opportunities designed to develop an expertise in innovative neurobiological research methods and a career as an independent AD and cognitive disorders investigator.