Quantitative Optical Imaging of Molecular Processes in Preclinical Cancer Models

描述（由申请人提供）：“临床前癌症模型中分子过程的定量光学成像”申请是应NCRR项目病理学和比较医学特别强调研究事业奖（SERCA, K01）的公告而提交的。越来越明显的是，没有一种单一的成像方式能够为诊断、预后和治疗效果提供足够的信息。候选人寻求获得生物医学成像方面的培训，以领导独立的研究事业，应用先进的光学成像方法和磁共振成像（MRI）来研究癌症的分子机制。具体的职业发展培训领域将包括癌症分子生物学、磁共振成像原理、生物医学成像原理和造影剂开发等课程。肿瘤靶向荧光探针分子成像原理，包括造影剂（小分子、大分子和纳米颗粒）和靶向片段（单克隆抗体、受体特异性蛋白、高亲和肽和可切割肽序列）的特性。候选人将接受磁共振成像的物理和生理基础以及灌注和扩散加权成像和动态对比增强MRI的实验程序的指导，包括成像剂的药代动力学测量和建模的方法和软件，包括消除，组织递送和清除，受体结合和酶活性。这些原理将应用于开发与传统和可活化分子探针互补的光学成像方法。人类癌症动物模型的实际方面，包括人类细胞和组织异种移植，转基因癌症模型，用于分子成像也将作为培训和研究的必要组成部分。候选人将在科学写作方面受到指导，包括提交科学手稿，以及在第4年提交至少一份r01级申请的目标。该培训将在华盛顿大学医学院进行，该校在生物医学研究，特别是生物医学成像方面处于世界领先地位。候选人将受到光学成像，磁共振成像和癌症生物学领域的杰出研究人员的指导和合作。光学成像是使用安全稳定的造影剂进行低成本、高通量临床前成像的一种极好的方法。光学成像使用荧光化合物，而不是放射性造影剂，在注射后的几天到几周内，可以看到全身的荧光化合物，没有明显的毒性。在注射后数天至数周内，可在全身检测到单独注射或以活化剂形式注射的多种药物，而无明显毒性。在拟议的工作中，荧光造影剂将研究靶向癌症特异性细胞表面受体和细胞外酶。这些生物标志物的表达将与治疗反应进行监测，以开发可用于临床前药物开发并最终转化为临床应用的定量方法。光学成像结果将与扩散加权和对比增强磁共振成像数据进行比较和结合，以协同癌症特征。结合培训和临床前成像研究将装备候选人的专业知识和经验，成为临床前成像研究领域的领导者。

DESCRIPTION (provided by applicant): The application "Quantitative optical imaging of molecular processes in preclinical cancer models" is submitted in response to the NCRR program announcement for the Special Emphasis Research Career Award (SERCA, K01) in Pathology and Comparative Medicine. It is becoming increasingly evident that no single imaging modality is capable of providing sufficient information for diagnosis, prognosis and therapeutic efficacy. The Candidate seeks to gain training in biomedical imaging to lead an independent research career applying advanced optical imaging methods and magnetic resonance imaging (MRI) to investigate the molecular mechanisms of cancer. Areas of specific career development training will include courses covering molecular biology of cancer, principles of magnetic resonance imaging and principles of biomedical imaging and contrast agent development. Principles of molecular imaging using cancer-targeted fluorescent probes, including characteristics of contrast agents (small molecules, macromolecules and nanoparticles) and targeting moiety (monoclonal antibodies, receptor-specific proteins, high affinity peptides and cleavable peptide sequences).The Candidate will receive instruction on the physical and physiologic basis of Magnetic Resonance Imaging and the experimental procedures for perfusion and diffusion weighted imaging and dynamic contrast-enhanced MRI, including methods and software for measuring and modeling pharmacokinetics of imaging agents, including elimination, tissue delivery and clearance, receptor binding and enzyme activity. These principles will be applied to develop complementary optical imaging methods with conventional and activatable molecular probes. The practical aspects of animal models of human cancer, including human cell and tissue xenografts, transgenic cancer models, for molecular imaging will also be included as a necessary component of the training and research. The Candidate will be mentored in scientific writing, including submission of scientific manuscripts, as well as grantsmanship with the goal of at least one R01-level application submitted in year 4. This training will take place at Washington University School of Medicine, a world leader in biomedical research, particularly biomedical imaging. The Candidate will be mentored by and collaborate with outstanding researchers in the fields of optical imaging, magnetic resonance imaging and cancer biology. Optical imaging is an excellent method for low cost, high-throughput preclinical imaging using safe and stable contrast agents. Rather than radioactive contrast agents, optical imaging uses fluorescent compounds that can be visualized throughout the body for days to weeks after injection with no evident toxicity. Multiple agents injected separately or in the form of activatable agents can be detected throughout the body for days to weeks after injection with no evident toxicity. In the proposed work, fluorescent contrast agents will be investigated that target cancer-specific cell-surface receptors and extracellular enzymes. The expression of these biomarkers will be monitored in relation to therapeutic response to develop quantitative methods that can be used for preclinical drug development and eventually translated to clinical use. Optical imaging results will be compared and combined with diffusion-weighted and contrast-enhanced magnetic resonance imaging data for synergistic cancer characterization. The combined training and preclinical imaging research will equip the Candidate with the expertise and experience to be a leader in the field of preclinical imaging research. PUBLIC HEALTH RELEVANCE (provided by applicant): The Candidate will receive training in cancer biology and biomedical imaging techniques through development of multimodal imaging approach to measure therapeutic response in animal models of breast cancer. Detection of therapeutic response early initiation can speed the clinical decision- making process and improve overall response. Non-invasive imaging techniques are needed for this purpose.