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

摘要 在发达国家，新生血管在导致失明的主要原因中发挥着关键作用， 包括湿性老年性黄斑变性(AMD)。在早期阶段，湿性AMD的特点是 分子变化。后来，脉络膜新生血管(CNV)发展，导致视网膜下出血， 伤痕累累，以及不可逆转的视力丧失。因此，在出血前的早期阶段检测湿性AMD 发展，可以提高视力。这项K08研究将开发和研究一种新型的多模分子 使用光声显微镜(PAM)、光学相干层析成像(OCT)和 荧光显微镜检测湿性AMD比目前使用分子可能更早的阶段 用造影剂观察α对β3整合素在新生血管中的作用。CNV将本地化并量化到10以下 微米级分辨率。这种实时的活体分子信息将允许靶向治疗和精确度 根据每个患者独特的分子表达量身定做的药物。 中心假设是αvβ3整合素的分子成像在早期将是敏感和特异的 脉络膜新生血管，可作为早期检测新生血管的生物标志物。 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整合素的多模式分子成像；以及3) 证明αvβ3整合素的分子成像可以在兔模型中更早地检测到新生血管。这个 这项研究的两个具体目的是：1)检验光声显微镜(PAM)可以安全地 显示脉络膜视网膜微血管，以及2)使用金定量分子成像的程度 靶向αvβ3整合素的纳米颗粒定位于CNV，并使CNV能够更早地可视化。 这项职业发展研究计划的长期目标是让调查人员发展技能 在高分辨率、多模式分子眼科成像方面的专业知识，以了解分子 导致脉络膜新生血管的机制。这将通过及早改善对患者的护理 检测诊断、精确医学和提高对基础生物学的理解。世界-- 来自密歇根大学的知名导师和顾问是各自领域的领导者，并 完全致力于指导候选人发展成为一名独立的研究员、临床医生和科学家。

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.