Imagine calling T-cells, macrophages, and antibodies into action by taking a simple pill that instantaneously programs both adaptive and innate arms of the immune system to attack a tumor or virus, preventing infection and halting disease. Such an approach could meet major unmet challenges in biomedical research and therapy. My goal is to develop novel approaches that allow innate and acquired immunity to be purposefully targeted to pathogens of interest. These studies build on recently revealed mechanisms of Toll-like receptor signaling, ideas concerning approaches of targeting their sensing abilities to pathogens of defined interest and insights gained from our own invention of chemically programmed antibodies. Ultimately, these studies will allow scientists to program a variety of immune cells and responses to attack pathogens of interest using a variety of mechanisms. We will apply these results to studies in cancer therapy. Furthermore, we will explore novel approaches that should allow for circulating immunoglobulins induced with covalent vaccines to be programmed to inhibit HIV-1 and flu virus entry. The vaccines that result from these studies may be of both prophylactic and therapeutics utility. I will develop novel chemical approaches aimed at learning how to purposefully target innate immunity, T- cells, and macrophages to defined pathogens. I will apply these developments to create new cancer therapies. I will develop a novel approach to orally available chemically programmed immunity. I will apply developments in orally available chemically programmed immunity towards new vaccine strategies for HIV-1 and flu.

Public Health Relevance

This research will explore new approaches towards directing immune responses to fight cancers and viruses. If successful, new therapies for cancer and HIV-1 will result. Additionally, a new approach to vaccines against HIV-1 and swine flu will be created.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1CA174426-05
Application #
8699729
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (01))
Program Officer
Bhatia, Kishor
Project Start
2010-09-30
Project End
2014-12-31
Budget Start
2014-08-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$420,211
Indirect Cost
$198,464
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gaj, Thomas; Sirk, Shannon J; Barbas 3rd, Carlos F (2014) Expanding the scope of site-specific recombinases for genetic and metabolic engineering. Biotechnol Bioeng 111:1-15
Gaj, Thomas; Sirk, Shannon J; Tingle, Ryan D et al. (2014) Enhancing the specificity of recombinase-mediated genome engineering through dimer interface redesign. J Am Chem Soc 136:5047-56
Gaj, Thomas; Barbas 3rd, Carlos F (2014) Genome engineering with custom recombinases. Methods Enzymol 546:79-91
Gaj, Thomas; Liu, Jia; Anderson, Kimberly E et al. (2014) Protein delivery using Cys2-His2 zinc-finger domains. ACS Chem Biol 9:1662-7
Patterson, James T; Asano, Shigehiro; Li, Xiuling et al. (2014) Improving the serum stability of site-specific antibody conjugates with sulfone linkers. Bioconjug Chem 25:1402-7
Gersbach, Charles A; Gaj, Thomas; Barbas 3rd, Carlos F (2014) Synthetic zinc finger proteins: the advent of targeted gene regulation and genome modification technologies. Acc Chem Res 47:2309-18
Sirk, Shannon J; Gaj, Thomas; Jonsson, Andreas et al. (2014) Expanding the zinc-finger recombinase repertoire: directed evolution and mutational analysis of serine recombinase specificity determinants. Nucleic Acids Res 42:4755-66
Liu, Jia; Gaj, Thomas; Patterson, James T et al. (2014) Cell-penetrating peptide-mediated delivery of TALEN proteins via bioconjugation for genome engineering. PLoS One 9:e85755
Gaj, Thomas; Mercer, Andrew C; Sirk, Shannon J et al. (2013) A comprehensive approach to zinc-finger recombinase customization enables genomic targeting in human cells. Nucleic Acids Res 41:3937-46
Gaj, Thomas; Gersbach, Charles A; Barbas 3rd, Carlos F (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31:397-405

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