Abstract

We have developed and applied a highly automated system of random germline mutagenesis to probe TLR signaling and resistance to viral infection in mice. The search for still more proteins involved in TLR signaling will continue as we have not yet approached saturation of the genome. Moreover, we have identified a number of genes with essential functions in these processes and propose to study them further. As new and essential components of the system are identified we will seek to understand them mechanistically using tools of biochemistry, cell biology, and genetics. We will also analyze the antagonistic relationship between MyD88 and Ticam1 by placing specific markers of the inhibitory influence exercised by each adaptor protein under surveillance. We envision close collaboration with our colleagues in Seattle, Stanford, La Jolla and Sydney, with whom we have worked for many years.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100627-09
Application #
9999450
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2012-09-01
Project End
2022-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Goltsev, Yury; Samusik, Nikolay; Kennedy-Darling, Julia et al. (2018) Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging. Cell 174:968-981.e15
Wagle, Mayura V; Marchingo, Julia M; Howitt, Jason et al. (2018) The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen. Cell Rep 24:577-584
Wang, Tao; Bu, Chun Hui; Hildebrand, Sara et al. (2018) Probability of phenotypically detectable protein damage by ENU-induced mutations in the Mutagenetix database. Nat Commun 9:441
Anchang, Benedict; Davis, Kara L; Fienberg, Harris G et al. (2018) DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity. Proc Natl Acad Sci U S A 115:E4294-E4303
Good, Zinaida; Sarno, Jolanda; Jager, Astraea et al. (2018) Single-cell developmental classification of B cell precursor acute lymphoblastic leukemia at diagnosis reveals predictors of relapse. Nat Med 24:474-483
McAlpine, William; Sun, Lei; Wang, Kuan-Wen et al. (2018) Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. Proc Natl Acad Sci U S A 115:E11523-E11531
Morin, Matthew D; Wang, Ying; Jones, Brian T et al. (2018) Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists. J Am Chem Soc 140:14440-14454
Johnson, Jarrod S; Lucas, Sasha Y; Amon, Lynn M et al. (2018) Reshaping of the Dendritic Cell Chromatin Landscape and Interferon Pathways during HIV Infection. Cell Host Microbe 23:366-381.e9
Burns, Tyler J; Frei, Andreas P; Gherardini, Pier F et al. (2017) High-throughput precision measurement of subcellular localization in single cells. Cytometry A 91:180-189
Burnett, Deborah L; Parish, Ian A; Masle-Farquhar, Etienne et al. (2017) Murine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immune dysregulation. Immunol Cell Biol 95:775-788

Showing the most recent 10 out of 121 publications