Kaestner, Klaus H., PhD
Functional analysis of the diabetes gene Hhex in endocrine pancreas development and physiology
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Genetics, Genetics\Type 2 Diabetes, Islet Biology, Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Hormone Secretion and Exocytosis
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
Recent genome wide association (GWA) studies discovered a significant association of a genomic region on chromosome 10 with type 2 diabetes and higher pediatric BMI. As the only transcription factor residing within this region, HHEX (Hematopoietically expressed homeobox) holds great potential to be the risk-conferring gene. However, GWAS data only tag a genomic region, but do not explain the mechanism by which the nearby candidate genes are involved in the state of diabetes, nor do they identify the causal variants. Therefore, functional studies are pivotal to translate GWAS results into potential therapeutic applications of HHEX. Known as a master regulator of several organs (heart, lung and liver, etc) in the mouse, Hhex has never been studied in the context of endocrine pancreas differentiation and physiology.
The goal of this project is to investigate whether Hhex is essential for the differentiation of endocrine islets and glycemic control in adulthood. Multiple genetic mouse models and shRNA will be employed to inactivate Hhex in endocrine progenitor cells and adult endocrine cells in mice and in human primary islets, respectively. Results from this project will position Hhex in the transcriptional network governing pancreas development, and assess its potential as a driver for stem cell differentiation towards fully functional islets for implantation. Furthermore, the studies on adult function of Hhex in glucose homeostasis will determine if and by what mechanism Hhex contributes to the pathogenesis of diabetes.
Mentor: Klaus H. Kaestner, PhD Postdoctoral Fellow: Jia Xang, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Human genetics research into the causes of type 2 diabetes has suggested that several genes might play a role in determining the risk of an individual of developing the disease. However, for most of these genes the molecular mechanism of how they might contribute to diabetes is unknown. We will address this knowledge gap by determining the specific role of the transcriptional regulator HHEX, one of these human diabetes genes, in the development and function of the endocrine pancreas. For this purpose, we will employ several mouse models with deficiency for the gene, and analyze their glucose metabolism and insulin secretion properties. Elucidating these molecular mechanisms will lead to earlier detection of diabetes and the development of novel treatments.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Understanding the detailed biology of the endocrine pancreas and insulin secretion will lead to the development of new pharmaceutical treatments for diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Several of our family members are afflicted with type 2 diabetes. We find the thought that some day our research might lead to new and improved treatments especially motivating.
In what direction do you see the future of diabetes research going?
I see two great opportunities for the future of diabetes research. For type 1 diabetes, recent progress in our understanding of the development of the pancreatic beta-cell has allowed us to make great strides towards improved beta-cell replacement therapy. These could be obtained not just from embryonic stem cells, but also from the reprogramming of mature pancreatic or other cell types.
For type 2 diabetes, the diabetes risk genes identified over the past five years, while not in themselves being useful for diabetes treatment, nevertheless point to new pathways that are important in establishing and maintaining a functional endocrine pancreas. By determining how these genes function, we will be able to determine which of them might be targeted for new drug development for the treatment of diabetes.
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