Abstract: Details of interactions between commensal bacteria and the human intestinal epithelia are increasingly being resolved at the molecular level. Gut microorganisms play key supporting roles in digestion, immunity, and enteric homeostasis, but their exchanges with intestinal epithelia cells (IECs) are at once symbiotic and confrontational. This environment of interspecies cross- communication has tremendous potential for therapeutic applications. If commensal bacteria can be engineered to mediate or inhibit specific signaling cascades, they could be used as in vivo relay stations: accessing the bloodstream, and thereby the entire host with highly specific signaling targets. The proposed work will examine the use of commensal bacteria for the controlled expression of an insulin-stimulating peptide GLP-1 into the intestinal epithelial cell space. The use of commensal strains for controlled release of GLP-1 into or near the mucosal lining of the gut may mediate a surrogate glucose regulatory mechanism. We have already shown this to be the case in mouse models of diabetes. The result, if translated to humans would be an orally-dosed treatment for type-1 diabetes that would potentially mediate the long term effects of diabetes and allow the patient to live normoglycemically for only pennies per day. Further, this research will develop a 3D culture model of the small intestinal villi. The model will differentiate intestinal stem cells into the four types of enterocyte within a 3D physiologically-relevant space. It will provide research in this area a much needed high throughput tool.

Public Health Relevance

This work will provide a potential treatment for type-1 diabetes that will eliminate the need for insulin injection and potentially eliminate the long-term complications associated with this disease. The treatment would cost only pennies per day.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
4DP2OD007155-02
Application #
8798503
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Basavappa, Ravi
Project Start
2010-09-30
Project End
2016-10-31
Budget Start
2015-07-01
Budget End
2016-10-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Cornell University
Department
Engineering (All Types)
Type
Earth Sciences/Resources
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Ladd, Mitchell R; NiƱo, Diego F; March, John C et al. (2016) Generation of an artificial intestine for the management of short bowel syndrome. Curr Opin Organ Transplant 21:178-85
Shaffiey, Shahab A; Jia, Hongpeng; Keane, Timothy et al. (2016) Intestinal stem cell growth and differentiation on a tubular scaffold with evaluation in small and large animals. Regen Med 11:45-61
Duan, Franklin F; Liu, Joy H; March, John C (2015) Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes 64:1794-803
Costello, Cait M; Sorna, Rachel M; Goh, Yih-Lin et al. (2014) 3-D intestinal scaffolds for evaluating the therapeutic potential of probiotics. Mol Pharm 11:2030-9
Costello, Cait M; Hongpeng, Jia; Shaffiey, Shahab et al. (2014) Synthetic small intestinal scaffolds for improved studies of intestinal differentiation. Biotechnol Bioeng 111:1222-32
Tran, Thua N N; Cui, Jinhui; Hartman, Mark R et al. (2013) A universal DNA-based protein detection system. J Am Chem Soc 135:14008-11
Goh, Yih-Lin; He, HongFei; March, John C (2012) Engineering commensal bacteria for prophylaxis against infection. Curr Opin Biotechnol 23:924-30