Imaging Complex Molecular Signatures in Cancer

描述(由申请人提供)： 近年来，分子成像作为一种对哺乳动物生理的各个方面进行成像的技术已被成功地利用。然而，使用这些非侵入性模式可以获得的信息是有限的，因为它依赖于单基因标记的表达和成像。虽然这些信息是有用的，但它可能会产生误导。例如，在疾病组织中过度表达的标志物在正常组织中也以时空方式表达，这使得在诊断环境中解释结果可能变得困难。一些研究已经证明，通过测量多种疾病相关基因表达变化的表达，对疾病的识别和分子分类具有高度的敏感性和特异性。因此，这些基因标记物中的一个以上同时过度表达更能预测疾病状态。到目前为止，分子成像无法一次成像多个标记物，需要同时使用不同的成像技术，或者需要快速连续成像具有较短生物半衰期的不同探针。这项拟议研究的目标是开发一种成像范式，允许同时检测和成像多个过度表达的癌症疾病靶点。在这里提出的实验中，我们将尝试将这些结构域连接到三个不同的配体上，通过原位酶重建同时靶标和成像三个不同的分子成像靶标。这一成像范例的应用将在体内进行，动物体内的肿瘤表达反式互补所需的一个子集或所有生物标记物。拟议的职业发展计划将为应聘者提供受保护的时间，通过学习新的实验室技术，参加选择性的教学课程，并在经验丰富的赞助商的密切监督下，在实验室和临床上扩大她在实验室和临床进行实验的知识和经验，以及咨询顾问、合作者、同事和大学内其他教师的意见，进一步发展她的研究技能。

DESCRIPTION (provided by applicant): Molecular imaging has successfully been utilized in the recent past as a technology for imaging various aspects of mammalian physiology. However, the information that can be obtained using these non-invasive modalities is limited since it relies on the expression and imaging of single gene markers. While this information is useful, it can be misleading. For example, markers over-expressed in diseases tissues are also expressed in normal tissues in a spatio-temporal manner making interpretation of the results in a diagnostic setting potentially difficult. Several studies have demonstrated a high degree of both sensitivity and specificity for the identification and molecular classification of diseases by measuring the expression of multiple disease-associated changes in gene expression. The simultaneous over-expression of more than one of these gene markers is, therefore, more predictive of the disease state. Until now, molecular imaging was unable to image more than one marker at a time, requiring either different imaging technologies to be utilized simultaneously or requiring different probes with short biological half-lives to be imaged in rapid succession. The goal of the proposed study is to develop an imaging paradigm that will allow the detection and imaging of multiple over-expressed cancer disease targets at the same time. In the experiments proposed here we will attempt to conjugate these domains to each of three different ligands to simultaneously target and image, via enzyme re-construction in situ, three different molecular imaging targets. Application of this imaging paradigm will be conducted in vivo with animals bearing tumors that express either a subset or all of the biomarkers required for trans complementation. The proposed career development plan will offer the candidate protected time to further develop her research skills by learning new laboratory techniques, taking selective didactic coursework, and expanding her knowledge and experience in the practical conduct of experimentation both in the laboratory and in the clinic under the close supervision of experienced sponsors with input from consultants, collaborators, colleagues, and other faculty within the University.