SPECIALIZED RESOURCE A: SMALL ANIMAL IMAGING CORE Core Director: Dr. Thomas Yankeelov,Ph.D. (Dr. Yankeelov will be assisted in directing the Core by Dr. Gore who will devote 5% effort to these duties. Additionally, Dr. Yankeelov will be assisted by Drs. Peterson and Does.) The overall goal of the Small Animal Imaging Core is to develop, implement, optimize, and validate quantitative' surrogate biomarkers of tumor treatment response. This parallels the overall goal of the VICMIC; namely, to develop and apply imaging approaches for the non-invasive, quantitative assessment of the molecular and cellular mechanisms of response to targeted treatment of tumors in vivo. The Imaging Core will be dedicated to providing scientific and technical resources and support for non-invasive imaging of small animal models of cancer in vivo and is fundamental to the success of each project described in this application: Projects supported by the Imaging Core are directed at employing novel, targeted therapies which will elicit molecular signatures that can be imaged via optical, SPECT, and PET methods and then complemented with the (downstream) physiological information obtained from ultrasound, MRI, and CT. Briefly, the goal of Project 1 (PI: Robert Coffey) is to assess non-invasively tumor response to targeted therapies which are expected to affect tumor burden, cell proliferation, apoptosis, and angiogenesis. Thus, imaging protocols have been designed to report on both the molecular signatures of colon cancer treatment response as well as the ensuing physiological changes. A similar approach will be applied to Project 2 (PI: Larry Marnett) which is focused on monitoring Cox-2 expression (molecular level) and tumor regression (physiologic level) following treatment with Cox-2 inhibitors. Project 3 (P.I. Dennis Hallahan's) uses phagedisplayed peptide libraries labeled with optical and nuclear probes to delineate responding from non-responding tumors (molecular); responding tumors will also yield physiologic changes measured by ultrasound and MRI. Project 4 (PI: Lynn Matrisian) focuses on developing optical and MRI beacons for detection of MMP activity (molecular) to report on tumor response which may then be correlated to changes in cellularity and vascularizaton (physiologic). In addition to providing the methods required by these projects, the Imaging Core will develop techniques that can augment these studies as well as support developmental projects. The equipment and personnel needed to support research by investigators from within the VICMIC will be provided by the Center for Small Animal Imaging (CSAI) (see Resources)). The CSAI provides a comprehensive array of dedicated resources for state-of-the-art studies of small animals in vivo using MRI, X-ray CT, optical, ultrasound and microPET, and microSPECT. The CSAI represents a major institutional commitment to develop and support small animal imaging. The facility is supported by an expert faculty dedicated to developing new and improved imaging methods and their applications, laboratory spaces for animal preparation and monitoring, computing resources for image analysis and processing, and an electronics workshop for development of instrumentation and other technical support. In December of 2006, the CSAI was relocated to a new 41,000 sq. ft. $21 million building dedicated to Imaging Science. Two developments have strengthened our position as a leading cancer imaging institution. In June of 2007, the Center received a NCI Small Animal Imaging Resource Program grant (PI: Gore) that provides funds for services and equipment to benefit existing grants and to increase efficiency, promote new research directions, and foster interactions. We believe this development significantly enhances the capabilities of the CSAI. Our SAIRP is heavily focused on cancer with approximately 80% of resources earmarked for cancer imaging. Additionally, we have recently formed a Cancer Imaging Group within the VUIIS to form a cohesive strategy in developing quantitative methods of cancer imaging. The group has elected quantitative synthesis of multi-modality imaging data as its target and designed a roadmap complete with 6 month benchmarks towards making this a reality. As indicated in the above discussion of the four primary projects, this focus has much synergy with the goals of this application. The cancer imaging group meets weekly to discuss and foster progress and the SAIRP has greatly enhanced the abilities of this group. With the establishment of the proposed ICMIC, the resources of the CSAI would be dedicated at least 70% to cancer studies in small animals for ICMIC applications. From our experience over the past 2 years of imaging in cancer studies of small animals, and have logged 1000's of hours of operations for this purpose. From our current users, over 60% of the operations are already being applied to NIH-funded studies of small animal models of cancer, including multiple projects of investigators of the proposed ICMIC. We will further develop the available infrastructure for cancer imaging, and will also advance and integrate new imaging technologies for the comprehensive evaluation and characterization of small animal models of cancer. Specific technological developments will be undertaken, but the funds for the ICMIC will be used mainly on supporting key personnel and operations. We also aim to allow the information obtainable from all imaging modalities to be combined with proteomic maps obtained from imaging mass spectrometry (MALDI), and histology. Thus, the overall aims of the imaging core are: 1. To develop, implement, optimize, and validate quantitative MR, optical, PET, SPECT, and US imaging metrics of tumor growth and treatment response. The flow chart presents an overview of this process. 2. To provide a knowledge-base and resources to guide ICMIC investigators in the selection and implementation of appropriate imaging technologies to address each investigators goals.