(taken directly from the application): The goal of this project is to produce a source of surrogate beta cells that will be suitable for the treatment of insulin dependent diabetes mellitus (IDDM). We have recently targeted insulin expression to the intermediate lobe (IL) of the pituitary of transgenic nonobese diabetic (NOD) mice, a model for human IDDM. The IL pituitary tissues from these mice secreted abundant amounts of insulin via a regulated secretory pathway, similar to islet beta cells. However, in contrast to the insulin-producing islet beta cells, the insulin-producing IL pituitaries were not attacked by cells of the immune system. Remarkably, transplantation of small amounts of the transgenic IL tissues into diabetic NOD mice resulted in the restoration of near-normoglycemia and the complete reversal of diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bone fide insulin has raised the potential of these cell types for the treatment of IDDM. The major objective of this project is to now introduce into the insulin-secreting IL tissues the ability to secrete insulin in response to glucose and other physiological secretagogues (e.g., meals). The requirements for glucose sensing will initially be tested utilizing a recombinant adenovirus gene delivery system. Subsequently, the optimal components will be stably expressed in the insulin-secreting IL tissues of NOD mice using transgenic mouse techniques. We will assess whether these bioengineered tissues, when transplanted into diabetic NOD mice, can lead to long term normalization of glucose homeostasis and whether they can still avoid the autoimmune destructive process targeted against beta cells in IDDM. We will evaluate, in collaboration with Project 4, the ability of these cells compared to the islets derived in Projects 1 and 3, to survive xenogeneic transplantation. The information gained from the other projects will be used, as needed, to further modify these bioengineered IL cells to enhance graft survival. These strategies may create a novel source of """"""""artificial beta cells"""""""" for diabetes treatment.
Showing the most recent 10 out of 14 publications
