Scherer, Philipp E, PhD
Inducible activation of the Xbpl unfolded protein response pathway: Implications for beta cell survival
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology\Hormone Secretion and Exocytosis
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2008
Project End Date: June 30, 2012
Inadequate production and secretion of insulin is the hallmark of diabetes which is the result of beta cell malfunction and beta cell death. As a professional secretory cell, the pancreatic beta cell is particularly sensitive to environmental perturbations leading to problems in the pathways that release insulin from the beta cell. These problems lead to the induction of the so-called 'unfolded protein pathways'. These pathways can protect the beta cell from further damage, but can also lead to further beta cell dysfunction and beta cell death.
Here, we want to test the role of one particular pathway that involves a protein called XBP-1. Dr. Deng will take advantage of a novel mouse model developed in my laboratory that enables her to activate sXBP-1 on command exclusively in beta cells. This will allow for the first time to probe the potentially highly protective effects of XBP-1 under metabolically challenging conditions for beta cells. The elucidation of mechanistic involvement of XBP-1 in beta cells will allow Dr. Deng to better understand the time course of the unfolded protein response in vivo and help her identify potential pharmacological interventions to promote survival of beta cells under diabetic conditions.
Mentor: Philipp Scherer, PhD Postdoctoral Fellow: Yingfeng Deng, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Type 2 diabetes is ultimately a beta cell disease in the course of which the beta cells fail due to multiple reasons. In particular, an overload of the secretory pathway due to the increased demand for insulin secretion is quite common. Here we test the hypothesis whether the constitutive activation of the unfolded protein response prior to the stress situation in the beta cell will convey protective effects on the beta cells.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It will tell us whether in principle the secretory pathway in the beta cell is a viable drug target to allow the beta cell to better cope with the increased stress associated with increased protein secretion.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My entire research program is focused around diabetes-related topics. Awards like this one that enable me to support a highly promising young post-doc are an integral part of our funding strategy and this project will be fully incorporated into our overall research strategy.
In what direction do you see the future of diabetes research going?
At the level of the fat cell, I believe the key will be to lean how to manipulate specific fat pads individually and learn how to drive excess calories into only a subset of the pads.
At the level of beta cells, we will need to learn how we can effectively protect beta cells from apoptosis and how to effectively increase the generation of new beta cells.
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