The beta-cells of the islets of Langerhans adjust their secretion of insulin in response to changes in the levels of metabolic fuels and insulinotropic hormones. Patients afflicted with non insulin-dependent diabetes mellitus (NIDDM), also known as type 2 diabetes, exhibit defective glucose-stimulated insulin secretion (GSIS). Restoration of normal glucose responsiveness or prevention of its loss could potentially restore or conserve normoglycemia in NIDDM.
Discovery of ligands specific to receptor(s) on a surface of a beta-cell will impact clinical issues including functional diagnosis and cell-specific gene delivery. Our group has successfully identified peptides that target beta-cells in vitro and in vivo. Given this demonstration, we are building off this capability to identify peptides that target dysfunctional beta-cells and to format them into platforms to deliver drugs, imaging agents and genes in vivo. Our goal is to generate a panel of cell-specific molecules that bind to and discriminate between normal, glucose responsive beta-cells and glucose nonresponsive beta-cells. These cell-targeting molecules will then be exploited for beta-cell specific delivery of genes and imaging agents. The goals of this research effort are to:
- Isolate cell-targeting peptides that bind in a cell-specific manner to glucose responsive and nonresponsive beta-cells.
- Although initial work is performed with animal models, we will also isolate peptides that bind to human islets in order to generate beta-cell targeting reagents of clinical utility.
- Optimize the peptides for affinity and cell specificity outside of the context of the phage scaffold.
- Utilize these constructs to deliver bioactive therapeutics to the target cells in vitro and in vivo.
This project is part of a program project grant with Christopher Newgard (Duke University), Dean Sherry (UT Dallas/UT Southwestern Medical Center), Thomas Kodadek (The Scripps Research Institute, Florida), and Paul Grayburn (Baylor Medical Center). We are also collaborating with Xiankai Sun (UTSW) for PET imaging of the pancreas using our delivery system.
More information can be found in the following publications:
Samli, Kausar N.; McGuire, Michael J.; Newgard, Christopher B.; Johnston, Stephen Albert; Brown, Kathlynn C. (2005) "Peptide-Mediated Targeting of the Islets of Langerhans" Diabetes, 54, 2103-2108.
Lin, Mai; Lubag, Angelo; McGuire, Michael J.; Seliounine, Serguei Y.; Tsyganov, Edward N.; Antich, Peter P.; Sherry, A. Dean; Brown, Kathlynn C.; Sun, Xiankai (2007) "Advances in molecular imaging of pancreatic beta cells" Frontiers in Biosciences.