Real-time In Vivo Visualization of the Molecular Processes in Choroidal Neovascularization

摘要 新生血管在发达国家致盲的主要原因中起着关键作用， 包括湿性年龄相关性黄斑变性（AMD）。在其早期阶段，湿性AMD的特征在于： 分子变化后来，脉络膜新生血管（CNV）的发展，导致视网膜下出血， 疤痕和不可逆转的视力丧失因此，在出血之前的早期阶段检测湿性AMD， 发展，可以改善视力。这项K 08研究将开发和研究一种新的多峰分子 使用光声显微术（PAM）、光学相干断层扫描术（OCT）的成像系统， 荧光显微镜检测湿性AMD的早期阶段比目前可能使用的分子 造影剂，以显示新生血管形成中的αvβ3整联蛋白。CNV将局部化并量化至低于10 微米分辨率。这种实时的体内分子信息将允许有针对性的治疗和精确度 根据每个病人独特的分子表达量身定制的药物。 中心假设是αvβ3整合素的分子成像在早期诊断中具有敏感性和特异性， 脉络膜新生血管形成，因此可以用作早期检测新生血管形成的生物标志物。 黄斑变性目的是：1）证明光声显微镜的安全性; 2） 使用PAM、OCT和荧光显微镜进行αvβ3整联蛋白的多模式分子成像;和3） 证明αvβ3整联蛋白的分子成像允许在兔模型中早期检测CNV。的 本研究的两个具体目的是：1）测试光声显微镜（PAM）可以安全地 使脉络膜视网膜微血管可视化，以及2）使用金的分子成像量化 靶向αvβ3整联蛋白的纳米颗粒定位于CNV，并使CNV的早期可视化成为可能。 本职业发展研究计划的长期目标是让研究者发展以下技能： 以及高分辨率、多模态分子眼科成像方面的专业知识， 导致脉络膜新生血管形成的机制。这将改善病人的护理， 检测诊断，精准医学，提高对基础生物学的理解。世界- 来自密歇根大学的著名导师和顾问是各自领域的领导者， 完全致力于指导候选人发展成为一个独立的调查临床科学家。

ABSTRACT Neovascularization plays a pivotal role in the leading causes of blindness in the developed world, including wet age-related macular degeneration (AMD). At its early stage, wet AMD is characterized by molecular changes. Later, choroidal neovascularization (CNV) develops, leading to subretinal hemorrhage, scarring, and irreversible vision loss. Thus, detection of wet AMD at an earlier stage, before the hemorrhage develops, can improve vision. This K08 research will develop and investigate a novel multimodal molecular imaging system using photoacoustic microscopy (PAM), optical coherence tomography (OCT), and fluorescence microscopy to detect wet AMD at an earlier stage than currently possible using molecular contrast agents to visualize αvβ3 integrin in neovascularization. CNV will be localized and quantified to sub-10 micron resolution. This real-time, in vivo molecular information will allow for targeted treatment and precision medicine tailored to each patient’s unique molecular expression. The central hypothesis is molecular imaging of αvβ3 integrin will be sensitive and specific in early choroidal neovascularization and can thus be used as a biomarker in early detection of neovascularization in macular degeneration. The objectives are to: 1) demonstrate the safety of photoacoustic microscopy; 2) perform multimodal molecular imaging of αvβ3 integrin using PAM, OCT, and fluorescence microscopy; and 3) demonstrate that molecular imaging of αvβ3 integrin allows for earlier detection of CNV in rabbit models. The two specific aims of this study are 1) Test the prediction that photoacoustic microscopy (PAM) can safely visualize the chorioretinal microvasculature, and 2) Quantify the extent that molecular imaging using gold nanoparticles targeting αvβ3 integrin localize to CNV and enable earlier visualization of CNV. The long-term goals of this career development research plan is for the investigator to develop the skills and expertise in high resolution, multimodal molecular ophthalmic imaging to understand the molecular mechanisms leading to choroidal neovascularization. This will improve the care of patients through early detection diagnosis, precision medicine, and improved understanding of fundamental biology. The world- renowned mentors and advisors from the University of Michigan are leaders of their respective fields and are fully commited to guiding the candidate's development into an independent investigator clinician scientist.