The goal of this project is to reconstruct human Type 1 diabetes in a mouse model system. This goal will be accomplished through the achievement of two specific aims. First, we will develop optimized immunodeficient mice that will provide an ideal vessel for the three human tissue types most relevant to T1D, namely the hematopoietic system, the thymus, and pancreatic beta-cells. These mice will be tested and validated using human fetal tissues. Second, we will generate each of the three tissue types listed above using directed differentiation of induced pluripotent stem cells derived from a panel of T1D patients. These T1D tissues will be implanted in the immunodeficient mice, and the mice will be monitored to observe the onset of autoantibody production and autoimmune destruction of beta-cells. This mouse model of human T1D will allow, for the first time, a detailed analysis of the development of autoimmunity in real time, thus opening the possibility of identifying novel therapeutic avenues for the treatment of the disease. This system will also be used to test the relative contributions of various risk alleles and environmental factors to the emergence of the T1D phenotype. The novel mouse strains and directed differentiation protocols developed as part of this project will be of great use not only for the study of T1D, but will be of broad use for the study of immunology and transplantation medicine across many diseases.

Public Health Relevance

This research will identify new ways to treat Type 1 diabetes. In addition to this, new strains of mice will be developed over the course of the project that will be of great use to a large community of researchers studying human immunology. Also as a part of this project, new methods will be developed to convert induced pluripotent stem cells into clinically useful cell types, such as blood cells and insulin-producing beta- cells, which could ultimately be transplanted into patients lacking those cells due to injury or disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
1R24DK092758-01
Application #
8183478
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M1))
Program Officer
Abraham, Kristin M
Project Start
2011-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$2,303,759
Indirect Cost
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Westacott, Matthew J; Farnsworth, Nikki L; St Clair, Joshua R et al. (2017) Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets. Diabetes 66:2436-2445
Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of ?-cells and type 1 diabetes. J Autoimmun 71:59-68
Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70
Chetty, Sundari; Engquist, Elise N; Mehanna, Elie et al. (2015) A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation. J Cell Biol 210:1257-68
Kayton, Nora S; Poffenberger, Gregory; Henske, Joseph et al. (2015) Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Am J Physiol Endocrinol Metab 308:E592-602
Guo, Shuangli; Dai, Chunhua; Guo, Min et al. (2013) Inactivation of specific ? cell transcription factors in type 2 diabetes. J Clin Invest 123:3305-16
Chetty, Sundari; Pagliuca, Felicia Walton; Honore, Christian et al. (2013) A simple tool to improve pluripotent stem cell differentiation. Nat Methods 10:553-6
Shultz, Leonard D; Brehm, Michael A; Garcia-Martinez, J Victor et al. (2012) Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12:786-98