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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.

项目摘要/摘要