The coalescence of two technologies promises to provide a new therapeutic approach in clinical care. Culture of pancreatic islets in low shear, randomized gravity rotating wall vessels, maintains differentiation with regulated insulin secretion. These islets are alginate coated to create a non-inflammatory immune haven. A single intraperitoneal implantation in diabetic patients results in normoglycemia for two years. This group is interested in the potential application of this new hormonal delivery system, based on peritoneal implantation of differentiated cell aggregates, to the problem of delivery of renal hormones 1-25-diOH vitamin D3 and erythropoietin. The form of vitamin D active in maintaining and protecting bone integrity is 1-25-diOH vitamin D3. Initially identified as deficient in dialysis patients, vitamin D is now thought to mediate the more common problems of steroid induced osteoporosis, and age-induced osteopenia. Erythropoietin is used to treat anemia of end-stage-renal disease, AIDS, and some forms of cancer. The hypothesis is that maintenance of renal hormone production by rotating wall vessel culture of renal epithelial cells will allow replacement therapy by implantation of cell aggregates into the peritoneal cavity of deficient animals. The first approach is to optimize cell culture conditions for the hormonal production that has already demonstrated by this laboratory. The second approach is to dissect the mechanisms of genetic expression by comparing gene expression in rotating wall vessel culture with and without reintroduction of shear stress. Last, the investigator will test whether implantation of renal cell aggregates restores hormonal activity in rats rendered hormonally deficient by 5/6 nephrectomy. Hence, this application aims to extend new technology by applying novel 3-dimensional tissue culture techniques to physiologically regulated delivery of hormonal replacement therapy.
|Collaco, Anne M; Rahman, Sima; Dougherty, Edward J et al. (2005) Circadian regulation of a viral gene promoter in live transgenic mice expressing firefly luciferase. Mol Imaging Biol 7:342-50|
|Hammond, T G; Benes, E; O'Reilly, K C et al. (2000) Mechanical culture conditions effect gene expression: gravity-induced changes on the space shuttle. Physiol Genomics 3:163-73|
|Kaysen, J H; Campbell, W C; Majewski, R R et al. (1999) Select de novo gene and protein expression during renal epithelial cell culture in rotating wall vessels is shear stress dependent. J Membr Biol 168:77-89|
|Hammond, T G; Goda, F O; Navar, G L et al. (1998) Membrane potential mediates H(+)-ATPase dependence of ""degradative pathway"" endosomal fusion. J Membr Biol 162:157-67|