申请内容对应指南研究方向二，为创建原创性可视化技术奠定基础。肿瘤血管正常化研究对于改善肿瘤与外界物质交换，研发肿瘤治疗新策略，具有重要意义。如何有效实现血管正常化，提升肿瘤干预效率，是关键问题。需要对肿瘤同时进行微观高分辨（看分子机制）与宏观大深度（界定肿瘤边界）成像研究。本课题通过光声成像方法创新，在同一系统上，实现跨尺度、多参量成像，为肿瘤血管正常化研究提供新手段，在功能与分子机制层面拓展对正常化问题的深入理解。具体，将通过光-声耦合物理方法创新，研发集成高分辨率与大穿透深度的跨尺度光声成像系统；实现对肿瘤血管形态、功能和相关蛋白分子活动，跨越微观到宏观的无创在体成像；建立血管正常化光声成像评价标准，在成像指导下，探索联合血管正常化的肿瘤治疗新策略。课题的实施，能够为重大研究计划提供分子与功能信息可视化新工具，有助于深入理解肿瘤演进过程分子机制，为指导肿瘤治疗新策略，提供新思路。

This proposal focuses on the 2nd research direction of the Grand Research Project, i.e. to develop innovative imaging technology. The development of new therapeutic strategies for cancer under the normalization of tumor vasculature has been rapidly emerging as a new opportunity to fight cancer. However, currently, there are still many unknown mechanisms critical to the ultimate success of these strategies. For example, how to make interventions, including anti-angiogenic therapy, more effective for normalizing the vasculature of tumor, and how to enhance the therapeutic efficacy through the extension and accurate prediction of the time window of vascular normalization. In this proposed research, we aim to develop and validate a new functional and molecular imaging technology—multi-scale, multi-parametric photoacoustic microscopy (MSMP-PAM)—that can offer new insights into these critical questions, and to explore novel cancer therapy strategies by combining conventional chemotherapy with tumor vascular normalization. Specifically, we will: (1) develop a new optical-ultrasonic beam-combination methodology to enable the integration of optical- and acoustic-resolution photoacoustic microscopy into one single system, offering capability of tumor imaging from molecular (with molecular probes) to cellular and tissue levels; (2) with this integrated multi-scale photoacoustic microscopy system, further develop methodologies and algorithms to extract the anatomic (microvessel density, tortuosity, etc.), functional (hemoglobin oxygen saturation, vascular permeability, etc.), and molecular (the over-expression of vascular endothelial growth factors, integrin, etc.) information to quantify and evaluate tumor vascular normalization under anti-angiogenic therapy; (3) conduct research on MSMP-PAM guided tumor vascular normalization to optimize methods for inducing vascular normalization, and to determine the corresponding time windows of the normalization; (4) under the guidance of MSMP-PAM, explore novel anti-cancer therapeutic strategies that combine conventional chemotherapy with tumor vascular normalization. In the conclusion of this proposed research, we expect to have: (1) a validated and application-ready multi-scale photoacoustic microscopy system that can potentially become a new vital imaging tool for the study of tumor vascular normalization; (2) an established model describing the relationship between the multiple functional and molecular photoacoustic parameters and tumor vascular normalization; (3) in-depth comprehension of tumor vascular angiogenesis and normalization; (4) new insights into the development of novel anti-tumor therapeutics combining conventional chemotherapy with tumor vascular normalization.