The central issue in aging research is learning why the thymus involutes with advancing age and whether this causes suppression of T- cell mediated immune events. Experimental evidence supports the argument that thymic involution is, in part, responsible for the decline in T cell functions of aged animals. There is also evidence supporting the notion that thymic involution is a reversible process. For example, implanted GH3 pituitary cells in aged rats have been shown to restore thymic morphology and functional activity. Thus, it would appear that techniques for repopulating the thymus may restore normal numbers of T lymphocytes. The reduction of thymic function may be the result of a reduction in the influx of progenitor T cells. Progenitor T cell infiltration into the thymus may, in turn, be regulated by the level of adhesion molecules, recognized by progenitor T cells, expressed in the lumen of thymic blood vessels. In addition, several independent observations suggest that thymic innervation contributes to the infiltration of progenitor T cells. It is plausible that the nervous system regulates the infiltration of progenitor T cells into the thymus by affecting the expression of adhesion molecules in the lumen of the thymic blood vessels. The goal of the proposed research is to identify and characterize the molecular mechanisms mediating adhesion of progenitor T cells to an endothelial monolayer and the ways in which neuromediators may regulate this process. The long-term objective of this work is to design new therapeutic strategies for the treatment of the degenerative aspects of aging. The proposed research plan is divided into two specific aims.
Specific Aim 1 examines the role of neuromediators in the adhesion of progenitor T cells. Neuromediators to be investigated include substance P (SP) and vasoactive intestinal peptide (VIP). This work will include the identification and characterization of specific receptor-ligan interactions mediating the adhesion of progenitor T cells to vascular endothelium.
Specific Aim 2 proposes and tests a mechanistic model and provides a quantitative framework to relate receptor-ligand interactions to rates of adhesion.
