The main purpose of this combined core is to provide a comprehensive service using state-of-the-art molecular and genetic methods to generate a variety of sophisticated knock-in, knock-out and transgenic mice for DRC investigators in their type 1 and type 2 diabetes research. We have successfully generated many lines of knock-in, knock-out and transgenic mice related to diabetes studies. It is noteworthy three ofthe highlights among all the animals generated during the previous funding cycle. Firstly, humanized mice, which carry 5 human genes by sequential re-targeting the same ES cells. The engraftment of human fetal liver-derived CD34+ hematopoietic stem cells can reach nearly 100% and last up to 9 months in this humanized mouse. Secondly, lines of innate immunity deficient NOD mice for the studies of type 1 diabetes, especially in association with exogenous and endogenous environmental factors. Using MyD88 deficient NOD mice generated by the core, DRC investigators demonstrated the importance of commensal flora in type 1 diabetes development and gut flora is an environmental modifier that influence diabetes onset Thirdly, lines of inflammsome deficient B6 mice for the studies of metabolic syndrome and type 2 diabetes. DRC investigators found that inflammasomes NLRP3 and NLRP6 negatively regulate NAFLD progression and obesity via modulation ofthe gut flora. This combined core consists of three subcores - Molecular, Gene targeting and Mouse breeding (MGM) components. Each subcore has its distinct function while all is interconnected. We will continue to provide our outstanding service for Yale DRC community. Moleculai: subcore will increase the use of improved high efficiency BAC mutagenesis to facilitate the generation of customized constructs for both type 1 and type 2 diabetes studies. Together with Molecular subcore. Gene targeting subcore will extend the humanized mouse model systems to include diabetes-related genes in order to evaluate preclinical testing of new therapies and/or vaccines, by our DRC investigators, for treatment and prevention type 1 diabetes. Mouse breeding subcore will backcross the improved humanized mouse lines to NOD background and several lines of infammasome deficient mice to pure NOD background forthe studies of type 1 diabetes.

Public Health Relevance

The creation of novel mouse models through genetic engineering provides new insights into the mechanisms responsible for the development of human diabetes and a means of testing novel therapies for the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Center Core Grants (P30)
Project #
5P30DK045735-22
Application #
8635339
Study Section
Special Emphasis Panel (ZDK1-GRB-S)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
22
Fiscal Year
2014
Total Cost
$296,594
Indirect Cost
$118,460
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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