Laboratory of Rupangi C. Vasavada, PhD

Numerous studies have shown that a reduction in the endogenous functional pancreatic beta cell mass is one of the major causes of almost every form of diabetes. Therefore, the development of therapies to preserve and regenerate endogenous beta cell mass and function holds great promise and potential for both Type 1 and Type 2 diabetes. This would be greatly facilitated through a better understanding of the signals and mechanisms governing normal beta cell development, growth and function, as well as through the discovery of agents with the ability to enhance beta cell growth and function without the potential for negative side-effects.

My laboratory has been interested in the role of two such growth factors, parathyroid hormone-related protein (PTHrP) and lactogens, in normal beta cell physiology and in the pathophysiological settings of diabetes and islet transplantation. We have used transgenic overexpression mouse models to demonstrate that these growth factors can enhance beta cell growth, survival and function in vivo. Currently, we are identifying the signaling and molecular pathways through which these factors enhance beta cell proliferation, survival and function. Furthermore, the effect of these factors in normal beta cell development, growth and function is being determined through beta cell-specific conditional knockout mice.

The translational goals of this research are to improve islet transplant outcomes and to induce beta cell regeneration in rodents, in vivo, either through the use of these growth factors or downstream target molecules activated by these factors. Finally, whether these factors can enhance human beta cell growth, survival and function is currently under investigation.

Recent Publications 

1. Cebrian A, Garcia-Ocaña A, Takane KK, Sipula D, Stewart AF, Vasavada RC.  Overexpression of parathyroid hormone-related protein inhibits pancreatic beta cell death in vivo and in vitro. Diabetes 51:3003-3013 (2002).
   
   
2. Garcia-Ocaña A, Takane KK, Reddy VT, Lopez-Talavera J-C, Vasavada RC, Stewart AF.  Adenovirus-mediated hepatocyte growth factor transfer to murine islets improves pancreatic islet transplant performance and reduces beta cell death. J Biol. Chem. 278:343-351 (2003).
   
   
3. Rao P, Cozar-Castellano I, Roccisana J, Vasavada RC, Garcia-Ocaña A.  Hepatocyte growth factor gene therapy for islet transplantation.  Expert Opin Biol Ther 4:507-518 (2004).
   
   
4. Fujinaka Y, Sipula D, Garcia-Ocaña A, Vasavada RC. Characterization of Mice Doubly Transgenic for Parathyroid Hormone-related Protein and Murine Placental Lactogen: A Novel Role for Placental Lactogen in Pancreatic Beta Cell Survival. Diabetes 53: 3120-3130 (2004).
   
   
5. Roccisana J, Reddy V, Vasavada RC, Gonzalez-Pertusa JA, Magnuson MA, Garcia-Ocaña A.  Targeted inactivation of HGF receptor, c-met, in beta cells leads to defective insulin secretion and Glut-2 downregulation without alteration of beta cell mass. Diabetes 54:2090-2102 (2005).
   
   
6. Vasavada RC, Gonzalez-Pertusa JA, Fujinaka Y, Fiaschi-Taesch NM, Cozar I, Garcia-Ocaña A. Growth factors and pancreatic beta cell proliferation. International Journal of Cell Biology and Biochemistry 38:931-950 (2006).
   
   
7. Cozar-Castellano I, Fiaschi-Taesch N, Bigatel TA, Takane KK, Garcia-Ocaña A, Vasavada RC, Stewart AF. Molecular control of cell cycle progression in the pancreatic beta-cell. Endocr Rev. 27:356-370 (2006).
   
   
8. Vasavada RC, Cozar-Castellano I, Sipula D, Stewart AF. Tissue-specific deletion of the retinoblastoma protein in the pancreatic beta cell has limited effects on beta cell replication, mass and function. Diabetes 56:57-64 (2007).
   
   
9. Fujinaka Y, Takane K, Yamashita H, Vasavada RC. Lactogens promote beta cell survival through JAK2/STAT5 activation and BclXL upregulation. J Biol Chem 282:30707-30717 (2007).
   
   
10. Vasavada RC, Wang L, Fujinaka Y, Takane KK, Rosa T, Mellado-Gil JM, Garcia-Ocaña A. Protein kinase C-ζ markedly enhances β-cell proliferation: An essential role in growth factor-mediated β-cell mitogenesis. Diabetes 56:2732-2743 (2007).

Vasavada lab members (present & past)

                                 
    Sheela Joshi            Katoura Williams         Nagesha Guthalu Kondegowda     Hugo Lin

 

                
Yuichi Fujinaka    Darinka Sipula             Lin Wang               Rubiliat Oluronbi        Takaya Matsushita

Insulin-stained pancreatic sections                                                                   Insulin (green) and propidium iodide
from normal & PTHrP-transgenic mice                                                              (red) stained pancreatic section

             

Signaling & molecular pathways through
which lactogens inhibit beta cell death

.......  

Signaling pathways through which PTHrP enhances beta cell function and proliferation

                                     Halloween Party

      

           Poster Presentation, 2007