The  combination  of  molecular  specific  contrast  agents  and  imaging systems can be applied both to disease diagnosis and to monitor the efficacy of therapeutics.  Here, we provide an overview of ongoing research using vital optical imaging for disease diagnosis.  An important focus of our work is to apply contrast agents and intravital imaging systems to study the initiation and progression of tumors in living animals.  Cancer metastasis is a complex  multistep  process  in  which malignant  cells  escape  from  a  primary  tumor,  invade  surrounding tissue, migrate through the extracellular matrix, and are transported via the circulatory system to establish secondary  tumors  at  distant  sites. Traditional  in vivo  studies  of  metastasis  only  detect  the beginning  and  end  points  of  metastasis. However, interdisciplinary approaches, coupling advances in molecular contrast agents and new in vivo real time microscopies can be used to study biological models, facilitating a complete in vivo analysis of metastasis as an ongoing process.  

As part of our renewal, we will collaborate with faculty from the Texas Medical Center to expand these efforts.  Drs. Patrick  and  Reece  have developed  novel  imaging strategies to  provide quantitative  three  dimensional maps of microvasculature from histologic  specimens.  We will combine these methods with intra-vital techniques currently under development to yield tools to assess microvasculature quantitatively in vivo.

Studies  of  biopsy specimens  undergoing multistep  tumorigenesis  have demonstrated  a  progression  of events that appears to be driven by  ongoing  genetic  instability. To  better  understand  the processes that drive genomic instability  and  clonal outgrowth  at  the  expense  of neighboring  normal  epithelial cells, the Hittelman laboratory has  initiated  in vitro studies utilizing  three  dimensional, organotypic tissue culutres.  For  example,  to  better understand  the  determinants  of tissue  take-over  in  the  lung, normal  human  bronchial epithelial  cells  (transfected with green or yellow fluorescence protein) are plated onto filters and grown to mimic lung  epithelium.  More advanced lung epithelial cells (labeled with a different fluorescence protein and transfected with other genes of interest) are then plated onto denuded spaces on the same filter and allowed to grow and compete with the normal bronchial cells for growth surface.  Intercellular  events  are  then  observed  over  time  using  an  inverted  confocal  laser scanning fluorescence microscope. In the current rendition of the model, the determinants of tissue takeover (e.g., matrix metalloproteinase expression at the leading edge, loss of tight junctions in the invaded  population)  can  only  be  examined  following  termination  of  the  experiment  using immunofluorescence analyses (using appropriate antibodies and confocal laser scanning microscopy) on fixed sections of the filter. Dr. Hittelman will establish new collaborations with Drs. Sokolov and Richards-Kortum to image contrast agents in combination with intravital microscopies to carry out these studies on living cell populations and follow specific events in space and time. 

Although  the  major  focus  of  our  program  is  the  use  of  vital  diagnostic  optical  imaging,  we  will expand our range of clinical collaborations to include other and multi-modal imaging techniques. As an example, we will work with Dr.  Mawlawi  to  compare  and  contrast  optical  imaging  approaches  to functional  imaging  using  Positron  Emission Tomography  (PET).  Dr. Mawlawi  is  an  expert  in  factors affecting  absolute  quantification  of  PET  images  such  as  partial  volume,  scatter,  and  patient  motion artifacts. His lab is developing novel techniques of image acquisition, correction and formation as well as non-rigid image registration, and feature extraction.  Additional  research  interests  include modeling  the  distribution  of  novel  radiotracers  to  image  specific  biochemical  processes  such  as metabolism, blood flow, receptor binding and expression. These opportunities will help students place their research in optical imaging in proper context of biologic and biomedical imaging as a whole.