Narrative The goal of this proposal is to develop a safe and effective way to prevent the immune response that leads to type I diabetes. Project Summary Type I diabetes (T1D) is an autoimmune disorder in which insulin-producing ?-cells are destroyed by autoreactive T cells. Once the islets are destroyed they do not readily regenerate, and patients must take replacement insulin to survive. More then 300,000 Americans have T1D, and another 30,000 will be diagnosed this year alone. Several genetic susceptibility markers have been identified for T1D, and antibodies specific for islet antigens can be detected in the blood before severe islet destruction takes place. Despite the improved ability to predict susceptibility to T1D, there is currently no way of stopping the onset of the disease. We intend to change this by developing a new type of vaccine that can be used to teach the immune system not to attack insulin-producing cells. Recently, we developed a new antigen targeting platform that exploits a novel class of non-coding RNAs, known as microRNA. By incorporating target sequences for specific microRNAs into an antigen-encoding gene, we could target expression of the antigen to specific cells types and cell states. Using this technology, we will develop a means to induce and expand islet-protective regulatory T cells (Tregs). Initial studies will be carried out to optimize the microRNA-regulated system to target antigen expression to antigen presenting cells in a manner that will promote the induction of Tregs. Following these studies, we will evaluate the effectives of our approach for preventing T1D in non-obese diabetic (NOD) mice. microRNA-regulated gene vaccines encoding islet antigens will be constructed, and NOD mice will be treated with the vaccines, and monitored for the development of diabetes. By inducing islet-protective Tregs, we expect to subdue the diabetogenic immune response and prevent T1D. This novel platform, which will be the first vaccine to target antigen specifically to tolerogenic cells, will provide a powerful means for preventing T1D in humans.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Director’s New Innovator Awards (DP2)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-B (O1))
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Chung, Chi-Yeh; Sun, Zhen; Mullokandov, Gavriel et al. (2016) Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis. Cell Rep 16:472-486
Agudo, Judith; Ruzo, Albert; Tung, Navpreet et al. (2014) The miR-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids. Nat Immunol 15:54-62
Miller, Jennifer C; Brown, Brian D; Shay, Tal et al. (2012) Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol 13:888-99
Mullokandov, Gavriel; Baccarini, Alessia; Ruzo, Albert et al. (2012) High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nat Methods 9:840-6
Agudo, Judith; Ruzo, Albert; Kitur, Kipyegon et al. (2012) A TLR and non-TLR mediated innate response to lentiviruses restricts hepatocyte entry and can be ameliorated by pharmacological blockade. Mol Ther 20:2257-67
Greter, Melanie; Helft, Julie; Chow, Andrew et al. (2012) GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36:1031-46
Baccarini, Alessia; Chauhan, Hemangini; Gardner, Thomas J et al. (2011) Kinetic analysis reveals the fate of a microRNA following target regulation in mammalian cells. Curr Biol 21:369-76
Jayaprakash, Anitha D; Jabado, Omar; Brown, Brian D et al. (2011) Identification and remediation of biases in the activity of RNA ligases in small-RNA deep sequencing. Nucleic Acids Res 39:e141
Baccarini, Alessia; Brown, Brian D (2010) Monitoring microRNA activity and validating microRNA targets by reporter-based approaches. Methods Mol Biol 667:215-33
Annoni, Andrea; Brown, Brian D; Cantore, Alessio et al. (2009) In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance. Blood 114:5152-61

Showing the most recent 10 out of 11 publications