Chronic inflammatory diseases such as asthma, rheumatoid arthritis, and Crohn's disease are thought to arise from an inappropriate immune response. In addition, a variety of types of cancers including gastric, colon and lung arise due to chronic inflammation. The innate immune system's interaction with bacteria is critical to these diseases. It has been shown that fragments of bacterial cell wall activate an innate immune response. The bacterial cell wall is a polymer of carbohydrates. The discrete structures of the activating fragments of bacterial cell wah are not known. In order to better understand the molecular basis of immunological diseases it is critical that a collection of well-defined carbohydrate probes be assembled. In this subproject, we propose to establish a library of structural defined carbohydrates derived from bacterial cell wall to identify small molecule probes ofthe innate immune response. We will use two different methods to produce the carbohydrate libraries: (1) chemical synthesis and (2) bioengineering of bacterial cell wall biosynthesis. We will then screen these libraries in our own laboratory to identify members that have immuno-stimulatory or immuno-inhibitory activity. In addition, we will print these libraries as microarrays so that we may probe for protein interactions. The microarray format will make it easy for us to distribute our libraries to other investigators. In addition, we will use the bacterial cell wall libraries to screen for novel biomarkers associated with Crohn's disease. This project takes a unique approach to addressing major problems in the field of innate immunity through the combination of chemical synthesis, bacterial bioengineering, molecular biology, biochemistry and our knowledge of innate immune signaling. The probes that are developed in this subproject will be useful in the development of new therapeutics for the treatment of inflammatory disorders.

Public Health Relevance

This research project will deepen scientific understanding of how the human body senses and responds to the presence of bacteria. Chronic inflammatory disorders, such as Inflammatory Bowel Disease, arise from an inappropriate immune response to bacteria. This research will develop a carbohydrate library to investigate the activation of the immune system and knowledge gained from this investigation should result in more effective treatment and diagnosis for inflammatory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM104316-04
Application #
9302811
Study Section
Special Emphasis Panel (ZGM1-TWD-A)
Project Start
Project End
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
$206,663
Indirect Cost
$65,870
Name
University of Delaware
Department
Type
Domestic Higher Education
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
McDonald, Nathan D; DeMeester, Kristen E; Lewis, Amanda L et al. (2018) Structural and functional characterization of a modified legionaminic acid involved in glycosylation of a bacterial lipopolysaccharide. J Biol Chem 293:19113-19126
Potocny, Andrea M; Riley, Rachel S; O'Sullivan, Rachel K et al. (2018) Photochemotherapeutic Properties of a Linear Tetrapyrrole Palladium(II) Complex displaying an Exceptionally High Phototoxicity Index. Inorg Chem 57:10608-10615
Xu, Feiyang; Shuler, Scott A; Watson, Donald A (2018) Synthesis of N-H Bearing Imidazolidinones and Dihydroimidazolones Using Aza-Heck Cyclizations. Angew Chem Int Ed Engl 57:12081-12085
Liao, Jennie; Guan, Weiye; Boscoe, Brian P et al. (2018) Transforming Benzylic Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts via C-N Bond Activation. Org Lett 20:3030-3033
Gosselin, Eric J; Rowland, Casey A; Balto, Krista P et al. (2018) Design and Synthesis of Porous Nickel(II) and Cobalt(II) Cages. Inorg Chem 57:11847-11850
Li, Jiejing; Perfetto, Mark; Neuner, Russell et al. (2018) Xenopus ADAM19 regulates Wnt signaling and neural crest specification by stabilizing ADAM13. Development 145:
Smith, Natalee J; Rohlfing, Katarina; Sawicki, Lisa A et al. (2018) Fast, irreversible modification of cysteines through strain releasing conjugate additions of cyclopropenyl ketones. Org Biomol Chem 16:2164-2169
Liang, Hai; Zhou, Guangfeng; Ge, Yunhui et al. (2018) Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus. Bioorg Med Chem 26:3453-3460
Wu, Pengcheng; Yap, Glenn P A; Theopold, Klaus H (2018) Structure and Reactivity of Chromium(VI) Alkylidenes. J Am Chem Soc 140:7088-7091
O'Brien, Jessica G K; Chintala, Srinivasa R; Fox, Joseph M (2018) Stereoselective Synthesis of Bicyclo[6.1.0]nonene Precursors of the Bioorthogonal Reagents s-TCO and BCN. J Org Chem 83:7500-7503

Showing the most recent 10 out of 93 publications