This project focuses on the delivery of cells of the hematopoietic system to sites of function. Specifically, it will take advantage of two recent observations in the laboratory which highlight mechanisms for enhancing the homing capability of primitive precursor cells (aim 1), and, inversely, mechanisms by which mature cells fail to home due to active repulsion from specific sites (aim 2). The former offers the potential for improving the efficiency of hematopoietic stem cell engraftment by ex vivo manipulation of cellular reagents. The latter provides a basis for understanding and potentially intervening in the relative immunologic unresponsiveness of the host to tumors. The ability to address questions of cell localization has largely been restricted by technology in the past. Most recently it has become possible to image cell trafficking in vivo with high resolution MR imaging and/or quantitatively with nuclear imaging in small animals. The use of the proposed in vivo imaging methods, coupled with the ability to alter the properties of the circulating cells via the gene transfer techniques, provides opportunities for true synergy that will greatly enhance the productivity of these efforts.
The specific aims are: 1. Define if altered expression of the chemokine receptors CXCR-4 or KIA expressed on hematopoietic stem cells results in the altered localization of hematopoietic stem cells in vivo, thereby potentiating engraftment, and 2. Determine if the movement of cells away from a chemokinetic stimulus participates in restricting immunologic attack of specific tumors in vivo. Achievement of these aims will provide methods of improving stem cell graft efficiency thereby enabling small volume stem cell transplants (aim 1) and a novel dimension of tumor immunology for targeted therapeutic development (aim 2).
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