Optical probe and instrumentation development for in vivo near-infrared fluorescence imaging of Alzheimer's disease

用于阿尔茨海默病体内近红外荧光成像的光学探针和仪器开发

基本信息

批准号：
10370719
负责人：
Steven Shuyu Hou
金额：
$ 12.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370719
关键词：
APP-PS1 Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Animals Antibodies Binding Biodistribution Blood - brain barrier anatomy Blood Vessels Brain Chemical Structure Confocal Microscopy Custom DAP kinase Dependence Deposition Development Disease Progression Drug Kinetics Dyes Early Diagnosis Environment Enzymes Fluorescence Fluorescent Dyes Fluorescent Probes General Hospitals Human Image Impaired cognition In Vitro Individual International Label Leadership Libraries Magnetic Resonance Imaging Massachusetts Measures Memory impairment Mentored Research Scientist Development Award Mentors Methods Microscope Microscopic Modeling Monitor Multi-modal optical imaging Mus Near-infrared optical imaging Neurodegenerative Disorders Neurofibrillary Tangles Nonionizing Radiation Optics Pathologic Penetration Performance Photons Positron-Emission Tomography Property Quantitative Structure-Activity Relationship Research Research Personnel Resolution Resources Scalp structure Senile Plaques Skin Structure System Techniques Testing Therapeutic Therapeutic Effect Time Tissues Training Transgenic Mice Validation Work abeta accumulation base cost cranium efficacy study extracellular falls fluorophore imaging approach imaging biomarker imaging modality imaging study imaging system in vivo in vivo evaluation in vivo imaging inhibitor instrumentation medical schools microscopic imaging molecular imaging mouse model multimodality multiphoton microscopy neurofibrillary tangle formation non-invasive imaging non-invasive monitor non-invasive optical imaging novel optical imaging optical spectra pre-clinical protein aggregation simulation single photon emission computed tomography small molecule libraries tau Proteins tau aggregation theranostics tool treatment response

项目摘要

PROJECT SUMMARY / ABSTRACT The main neuropathological hallmarks of Alzheimer's disease (AD) are the extracellular accumulation of amyloid plaque deposits and intracellular formation of neurofibrillary tangles (NFTs). To enable the study of disease progression and the effect of therapeutics in preclinical mouse models of AD, there is an urgent need for non- invasive methods of imaging both hallmarks in the living brain. The most established non-invasive imaging approaches at the whole animal level are magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). However, only optical techniques like near- infrared (NIR) fluorescence imaging have the theoretical spatial resolution to image individual amyloid plaques and NFTs. In contrast to PET and SPECT, NIR fluorescence has the additional advantage of using safe, non- ionizing radiation. Previous NIR fluorescence probes for AD have mostly emitted in the 600-650 nm wavelength range. While these probes can be used to provide low resolution, bulk estimates of AD pathology burden in vivo and to distinguish between AD mice and wildtype controls, they lack the ability to provide absolute quantitation and cannot be used to image non-invasively with microscopic resolution. To enable non-invasive optical imaging through the intact scalp and intact skull of mice, the wavelength of the fluorescent probe needs to be shifted into the NIR-II spectrum (1,000-1,700 nm). At these longer wavelengths, the penetration depth through tissue is increased dramatically while the background caused by intrinsic autofluorescence is minimized. Here we propose to develop and identify candidate probes for NIR-II imaging by employing two complimentary strategies. In the first approach, we will modify the chemical structure of a promising candidate probe, with existing affinity for amyloid plaques and NFTs to enhance its binding affinity and NIR-II fluorescence emission. In the second approach, we will screen an existing chemical library of > 650 NIR fluorophores using chemical structure-activity modeling and in vitro and in vivo characterization. To image our candidate NIR-II fluorophores in vivo, we will build a custom multi-modal microscope combining NIR confocal and multiphoton microscopy and fully characterize its performance with simulations and experimental validation. We will conduct longitudinal, in vivo imaging studies in AD mice to validate our developed probes and instrumentation and demonstrate for the first time non-invasive monitoring of AD pathology with microscopic resolution. The excellent scientific environment and world-class resources provided by the Massachusetts General Hospital and Harvard Medical School, as well as the internationally recognized leadership of the applicant's mentors, along with the expertise of the proposed collaborators, will be key to the successful completion of the proposed research. This K01 award will be instrumental for the applicant to strengthen his skillset with training in optical probe development and in vivo imaging in AD mice and to take the next steps towards becoming an independent researcher.

项目概要/摘要阿尔茨海默病（AD）的主要神经病理学特征是淀粉样蛋白的细胞外积累斑块沉积和细胞内神经原纤维缠结（NFT）的形成。促进疾病研究 AD 临床前小鼠模型的进展和治疗效果，迫切需要非对活体大脑中的这两个特征进行成像的侵入性方法。最成熟的非侵入性成像整个动物水平的方法有磁共振成像 (MRI)、正电子发射断层扫描 (PET) 和单光子发射计算机断层扫描 (SPECT)。然而，只有光学技术，如近红外 (NIR) 荧光成像具有对单个淀粉样斑块进行成像的理论空间分辨率和 NFT。与 PET 和 SPECT 相比，NIR 荧光具有使用安全、非电离辐射。以前用于 AD 的 NIR 荧光探针大多在 600-650 nm 波长范围内发射范围。虽然这些探针可用于提供低分辨率、体内 AD 病理负担的批量估计为了区分 AD 小鼠和野生型对照，它们缺乏提供绝对定量的能力并且不能用于以显微分辨率进行非侵入性成像。实现非侵入式光学成像通过小鼠完整的头皮和完整的头骨，荧光探针的波长需要转换为 NIR-II 光谱（1,000-1,700 nm）。在这些较长的波长下，穿过组织的穿透深度为显着增加，同时由固有自发荧光引起的背景被最小化。在这里我们建议通过采用两种互补的策略来开发和识别 NIR-II 成像的候选探针。在第一种方法中，我们将修改具有现有亲和力的有前途的候选探针的化学结构用于淀粉样斑块和 NFT，以增强其结合亲和力和 NIR-II 荧光发射。在第二个方法，我们将使用化学结构-活性筛选现有的超过 650 个 NIR 荧光团的化学库建模以及体外和体内表征。为了对我们的候选 NIR-II 荧光团进行体内成像，我们将构建结合近红外共焦和多光子显微镜的定制多模态显微镜，并完全通过模拟和实验验证来表征其性能。我们将进行纵向、体内 AD 小鼠成像研究，以验证我们开发的探针和仪器，并首次进行演示具有显微分辨率的 AD 病理学时间非侵入性监测。优良的科研环境以及麻省总医院和哈佛医学院提供的世界一流资源，以及申请人导师的国际公认的领导力，以及申请人的专业知识拟议的合作者将是成功完成拟议研究的关键。此次K01奖将通过光学探针开发和体内培训，有助于申请人加强其技能对 AD 小鼠进行成像，并采取下一步措施成为一名独立研究人员。