The proposed resource will generate a complete microarray dissection of gene expression in the mouse immune system, focused on primary cells ex vivo, in basal conditions or in response to genetic or environmental perturbations. A group of immunology experts will prepare, under standardized conditions, RNA from 175 populations of the innate and adaptive immune systems. These will include all lymphoid cell types, their precursors, and their variants in lymphoid organs and in different tissues, as well as the main myeloid lineages (DC, macrophages, neutrophils) and immunologically relevant stroma. Genome-wide expression profiles will be obtained from these RNAs by high-throughput microarray technology. In addition, we will generate expression profiles for T and B lymphocytes, Treg and NK cells from a panel of 48 inbred mouse strains, and segregating intercross animals (F2 and Heterogeneous Stock mice), providing a unique perspective on genomic variability in the Mus species. We will use these data to define the connectivity between genes and the regulatory interactions that occur in the operation of the immune system, using sophisticated computational tools that have proven very powerful in microbial systems; we will identify """"""""gene signatures"""""""" that characterize lymphoid lineages and the progression through differentiation steps. The computational predictions will then be tested/validated by modulating the expression of key genes by RNA interference, using lentiviral vectors to introduce RNAi effectors into mouse stem cells or embryos. The compendium of expression profiles, strain variability and the description of genomic networks and signatures will be made publicly accessible via electronic means, with rapid data release on the ImmGen site. In addition, we will develop, evaluate and deploy novel interactive methods for visual analysis, using sophisticated graphic vocabularies from the scientific visualization field. This resource should prove very useful to support investigations of the normal and pathological immune system. We will use high-throughput genomic, bioinformatic and computer graphic technologies to determine, uniformly and reliably, the complete profiles and regulation of gene activity in the immune system. This will form an essential foundation for the exploration of immune and autoimmune diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Resource-Related Research Projects (R24)
Project #
1R24AI072073-01A1
Application #
7320020
Study Section
Special Emphasis Panel (ZAI1-SV-I (M2))
Program Officer
Chiodetti, Lynda
Project Start
2007-09-18
Project End
2011-08-31
Budget Start
2007-09-18
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$965,906
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Stubbington, Michael J T; Rozenblatt-Rosen, Orit; Regev, Aviv et al. (2017) Single-cell transcriptomics to explore the immune system in health and disease. Science 358:58-63
ImmGen Consortium (2016) Open-source ImmGen: mononuclear phagocytes. Nat Immunol 17:741
Cortez, Victor S; Cervantes-Barragan, Luisa; Robinette, Michelle L et al. (2016) Transforming Growth Factor-? Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands. Immunity 44:1127-39
Mostafavi, Sara; Yoshida, Hideyuki; Moodley, Devapregasan et al. (2016) Parsing the Interferon Transcriptional Network and Its Disease Associations. Cell 164:564-78
Dwyer, Daniel F; Barrett, Nora A; Austen, K Frank et al. (2016) Expression profiling of constitutive mast cells reveals a unique identity within the immune system. Nat Immunol 17:878-87
Robinette, Michelle L; Fuchs, Anja; Cortez, Victor S et al. (2015) Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat Immunol 16:306-17
Mostafavi, Sara; Ortiz-Lopez, Adriana; Bogue, Molly A et al. (2014) Variation and genetic control of gene expression in primary immunocytes across inbred mouse strains. J Immunol 193:4485-96
Desch, A Nicole; Gibbings, Sophie L; Clambey, Eric T et al. (2014) Dendritic cell subsets require cis-activation for cytotoxic CD8 T-cell induction. Nat Commun 5:4674
Ericson, Jeffrey A; Duffau, Pierre; Yasuda, Kei et al. (2014) Gene expression during the generation and activation of mouse neutrophils: implication of novel functional and regulatory pathways. PLoS One 9:e108553
Jojic, Vladimir; Shay, Tal; Sylvia, Katelyn et al. (2013) Identification of transcriptional regulators in the mouse immune system. Nat Immunol 14:633-43

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