A Wireless Multi-function Microscope for Lifetime Imaging of the Brain Tumor Vasculome

用于脑肿瘤血管终身成像的无线多功能显微镜

基本信息

批准号：
10321899
负责人：
Arvind P Pathak
金额：
$ 41.76万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-12 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321899
关键词：
3D Print Alzheimer&apos s Disease Anesthesia procedures Anesthetics Angiogenesis Inhibitors Animals Arteries Biological Markers Blood Vessels Brain Neoplasms CD47 gene Cells Cerebrovascular Circulation Clinical Custom Data Development Devices Disease Drug Delivery Systems Dyes Electroencephalography Exhibits Fluorescence Gene Expression Glioblastoma Glioma Goals Histologic Histology Hour Image Imaging Device Immune Evasion Immune response Immunocompetent Immunosuppression Immunotherapy Knock-out Lasers Life Cycle Stages Lighting Magnetic Resonance Imaging Malignant neoplasm of brain Maps Measurement Mediating Microscope Mission Modeling Morphology Motivation Mus Neuraxis Optics Pathway interactions Patients Perfusion Phenotype Physiological Play Public Health Quail Research Resistance Resolution Role Signal Transduction Stroke Structure System Time Treatment Efficacy Tumor-associated macrophages Tumor-infiltrating immune cells United States National Institutes of Health Validation Vascular remodeling Veins Wireless Technology Xenograft procedure angiogenesis anticancer research awake behavioral study blood vessel development brain tumor imaging cancer imaging cellular engineering cerebral blood volume cerebral microvasculature clinically relevant design fluorescence imaging fluorophore imaging modality imaging system immunoregulation in vivo in vivo imaging insight miniaturize neoplastic cell neuroimaging novel therapeutics operation optical imaging optogenetics overexpression patient derived xenograft model pre-clinical real-time images recruit sensor therapy resistant transmission process treatment response treatment strategy tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions wireless wireless fidelity wireless transmission

项目摘要

ABSTRACTPreclinical and clinical evidence has shown that brain tumors can alter the structure and function of the central nervous system microvasculature (i.e. CNS vasculome) during progression, therapy and the emergence of therapeutic resistance. Brain tumor progression related vasculome remodeling occurs via angiogenesis (i.e. new blood vessel formation). In contrast, non-angiogenic pathways such as ‘co-option’ (i.e. tumor cells hijacking extant blood vessels) and ‘immunomodulation’ (i.e. vascular changes induced by the infiltration of immune cells) are involved in antiangiogenic resistance and immunotherapy evasion, respectively. To elucidate the role of these angiogenic and non- angiogenic pathways on brain tumor progression and therapeutic response necessitates the development of imaging tools that can characterize early to advanced in vivo changes in the CNS vasculome (i.e. over the lifetime of the disease). Therefore, our goal is to build a wireless ‘plug-n-play’ multichannel microscope capable of imaging structural/functional microvascular (~7-10 µm) changes in vivo, over the entire lifetime of a brain tumor. We propose to exploit advances in miniaturized optics, image sensor design and wireless technology to fabricate a miniature, wireless microscope with three channels: fluorescence (FL) to image fluorescent brain tumor cells or dyes; intrinsic optical signals (IOS) to image cerebral blood volume (CBV) and intravascular oxygenation (HbSat); and laser speckle contrast (LSC) to image cerebral blood flow (CBF). Guided by compelling preliminary data, we will pursue the following Specific Aims: (1) Develop a tether-free multichannel microscope with on-chip compressed sensing and wireless transmission; (2) Characterize the in vivo vasculome in angiogenic and co-optive patient-derived (PDX) brain tumor models over their lifetime; and (3) Characterize in vivo changes in the vasculome induced by the immune microenvironment of brain tumors. Under Aim1 we will fabricate a specialized image sensor with compressed sensing for ultra-low power wireless operation. After validation against an equivalent benchtop imaging system, we will image the CNS vasculome in healthy mice without the confounding effects of anesthetics. This will include identifying microvessel type (i.e. artery vs. vein) with FL, quantifying vascular morphology and HbSat with IOS, perfusion with LSC, and mapping ‘microvascular connectivity’ by correlating CBV (or CBF) fluctuations in microvessels. Under Aim2 we will characterize differences in the CNS vasculomes of clinically relevant angiogenic and co-optive patient-derived xenografts, and assess if the former exhibits larger disruptions in microvascular connectivity due to vascular remodeling. Under Aim3, we will characterize in vivo differences in the CNS vasculomes of wild-type and non-immunosuppressed xenografts, to determine if alleviating immunosuppression increases CBV/CBF/HbSat and promotes recruitment of tumor associated macrophages (TAM). We will create a versatile 3D printed plug-n-play wireless microscope that permits neuroimaging in freely behaving animals at any time, for any duration, during any task or physiological recording (e.g. EEG). As this microscope can be customized to any fluorophore, modified for optogenetics or drug delivery, and used for behavioral studies, we believe it will usher in a new era of brain cancer research, with utility in diseases involving the CNS vasculome (e.g. stroke, Alzheimer’s disease).

摘要临床前和临床证据表明，脑肿瘤可以改变大脑的结构和功能。进展、治疗和出现过程中的中枢神经系统微血管（即 CNS 血管组）治疗抵抗。脑肿瘤进展相关的血管重塑通过血管生成（即新血液）发生。相比之下，非血管生成途径，例如“共同选择”（即肿瘤细胞劫持现有血液）。血管）和“免疫调节”（即免疫细胞浸润引起的血管变化）参与分别阐明这些血管生成抵抗和免疫治疗逃避的作用。血管生成途径对脑肿瘤进展和治疗反应的影响需要成像技术的发展可以表征中枢神经系统血管组早期到晚期体内变化的工具（即在疾病的整个生命周期中）。因此，我们的目标是构建一种无线“即插即用”多通道显微镜，能够对结构/功能进行成像我们建议利用脑肿瘤整个生命周期中体内微血管（~7-10 µm）的变化。微型光学器件、图像传感器设计和无线技术，可制造微型无线显微镜三个通道：荧光（FL）用于成像荧光脑肿瘤细胞或染料（IOS）用于成像；脑血容量 (CBV) 和血管内氧合 (HbSat) 以及激光散斑对比 (LSC) 进行脑成像在令人信服的初步数据的指导下，我们将追求以下具体目标： (1) 制定一个 (2) 表征血管生成和选择性患者衍生（PDX）脑肿瘤模型在其一生中的体内血管组； (3)表征脑肿瘤免疫微环境诱导的血管组的体内变化。目标1 我们将制造一种具有压缩传感功能的专用图像传感器，用于超低功耗无线操作。通过对等效台式成像系统的验证，我们将对健康小鼠的中枢神经系统血管组进行成像，而无需使用这将包括通过 FL 识别微血管类型（即动脉与静脉）、量化。使用 IOS 测量血管形态和 HbSat，使用 LSC 进行灌注，并通过关联绘制“微血管连接” 在 Aim2 下，我们将描述临床 CNS 血管组的差异。相关的血管生成和选择性患者来源的异种移植物，并评估前者是否表现出更大的破坏在 Aim3 下，我们将描述中枢神经系统的体内差异。野生型和非免疫抑制异种移植物的血管组，以确定是否减轻免疫抑制增加 CBV/CBF/HbSat 并促进肿瘤相关巨噬细胞 (TAM) 的募集。 3D 打印的即插即用无线显微镜，可随时对自由行为的动物进行神经成像持续时间，在任何任务或生理记录（例如脑电图）期间，由于该显微镜可以针对任何荧光团进行定制，经过修改用于光遗传学或药物输送，并用于行为研究，我们相信它将迎来大脑的新时代癌症研究，可用于涉及中枢神经系统血管的疾病（例如中风、阿尔茨海默病）。