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:
  • 金额:
    $ 41.76万
  • 依托单位:
  • 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

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,脑肿瘤可以改变脑组织的结构和功能, 中枢神经系统微血管系统(即CNS血管组)在进展、治疗和出现 治疗抵抗脑肿瘤进展相关的血管重建通过血管生成(即新血)发生 血管形成)。相比之下,非血管生成途径,如“共选择”(即肿瘤细胞劫持现存的血液 血管)和“免疫调节”(即由免疫细胞浸润诱导的血管变化)参与 抗血管生成抗性和免疫治疗逃避。为了阐明这些血管生成和非血管生成的作用, 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CNS血管组中早期至晚期体内变化的工具(即在疾病的整个生命周期内)。 因此,我们的目标是建立一个无线的“即插即用”多通道显微镜,能够成像结构/功能 在脑肿瘤的整个生命周期中,微血管(~7-10 µm)在体内发生变化。我们打算利用 小型化光学、图像传感器设计和无线技术,以制造具有 三个通道:荧光(FL)成像荧光脑肿瘤细胞或染料;内在光学信号(IOS)成像 脑血容量(CBV)和血管内氧合(HbSat);以及激光散斑对比度(LSC)以成像脑 血流量(CBF)。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)开发一个 具有片上压缩传感和无线传输的无系绳多通道显微镜;(2)表征 血管生成和共视患者来源(PDX)脑肿瘤模型中的体内血管组;以及 (3)表征脑肿瘤免疫微环境诱导的血管组体内变化。下 目标1我们将制作一个专用的图像传感器与压缩传感器的超低功耗无线操作。后 通过与等效台式成像系统的对比验证,我们将对健康小鼠的CNS血管组进行成像, 麻醉剂的混淆效应。这将包括识别FL的微血管类型(即动脉与静脉),定量 血管形态和HbSat与IOS,灌注与LSC,并通过相关性映射“微血管连接” 微血管中的CBV(或CBF)波动。在目标2下,我们将描述临床上 相关的血管生成和共选择的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, 微血管连接由于血管重塑。在目标3下,我们将描述CNS中的体内差异 野生型和非免疫抑制异种移植物的血管体,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。我们将创造一个多功能的 3D打印即插即用无线显微镜,允许在任何时间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EEG)期间。由于这种显微镜可以定制任何荧光团, 经过光遗传学或药物输送的修改,并用于行为研究,我们相信它将迎来一个新的大脑时代。 癌症研究,可用于涉及CNS血管的疾病(例如中风、阿尔茨海默病)。

项目成果

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Arvind P Pathak其他文献

Arvind P Pathak的其他文献

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{{ truncateString('Arvind P Pathak', 18)}}的其他基金

Image-based Systems Biology of Vascular Co-option in Brain Tumors
脑肿瘤血管选择的基于图像的系统生物学
  • 批准号:
    10681077
  • 财政年份:
    2023
  • 资助金额:
    $ 41.76万
  • 项目类别:
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
  • 批准号:
    10539279
  • 财政年份:
    2019
  • 资助金额:
    $ 41.76万
  • 项目类别:
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
  • 批准号:
    9914541
  • 财政年份:
    2019
  • 资助金额:
    $ 41.76万
  • 项目类别:
Multiscale Image-based Modeling of Antiangiogenic Resistance in Breast Cancer
基于图像的乳腺癌抗血管生成耐药性的多尺度建模
  • 批准号:
    8941820
  • 财政年份:
    2015
  • 资助金额:
    $ 41.76万
  • 项目类别:
A Wireless Laser Speckle and Fluorescence Imager for In vivo Brain Tumor Imaging
用于体内脑肿瘤成像的无线激光散斑和荧光成像仪
  • 批准号:
    8491065
  • 财政年份:
    2013
  • 资助金额:
    $ 41.76万
  • 项目类别:
A Wireless Laser Speckle and Fluorescence Imager for In vivo Brain Tumor Imaging
用于体内脑肿瘤成像的无线激光散斑和荧光成像仪
  • 批准号:
    8735101
  • 财政年份:
    2013
  • 资助金额:
    $ 41.76万
  • 项目类别:
A LECTIN-CONTRAST AGENT FOR MULTIMODALITY MOLECULAR IMAGING OF TUMOR ANGIOGENESIS
用于肿瘤血管生成多模式分子成像的凝集素造影剂
  • 批准号:
    7597120
  • 财政年份:
    2008
  • 资助金额:
    $ 41.76万
  • 项目类别:
A LECTIN-CONTRAST AGENT FOR MULTIMODALITY MOLECULAR IMAGING OF TUMOR ANGIOGENESIS
用于肿瘤血管生成多模式分子成像的凝集素造影剂
  • 批准号:
    7470274
  • 财政年份:
    2008
  • 资助金额:
    $ 41.76万
  • 项目类别:
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