AID	Name	Type	Comment
588850	uHTS identification of cystic fibrosis induced NFkb Inhibitors in a fluoresence assay	screening	Primary Screen
624343	Dose Response confirmation of uHTS small molecule hits for cystic fibrosis induced NFkb Inhibitors in a PAF-induced IL8 counterscreen	confirmatory
624344	Dose Response confirmation of uHTS small molecule hits for cystic fibrosis induced NFkb Inhibitors in a panel assay	confirmatory
624347	Dose Response confirmation of uHTS small molecule hits for cystic fibrosis induced NFkb Inhibitors in a TNFa-induced IL8 counterscreen	confirmatory
602141	uHTS determination of small molecule cytotoxicity in a fluorescence assay to identify cystic fibrosis induced NFkb Inhibitors	screening
602472	Single concentration confirmation of uHTS hits for cystic fibrosis induced NFkb Inhibitors in a fluoresence assay	screening
651592	SAR analysis of molecule cystic fibrosis induced NFkb Inhibitors in a panel assay	confirmatory

Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: IR21 NS061743-01
Assay Provider: Rangan Maitra, Ph.D., RTI International University

The inflammatory response in Cystic Fibrosis (CF) is a complex interplay between several factors. It has been suggested that pro-inflammatory cytokines are elevated in the epithelial lining fluid samples of CF patients(1). Conversely, expressions of anti-inflammatory cytokines are reduced(2). 90% of all CF deaths occurs from defective lung function. The activation of NFkB via toll-like receptors following bacterial infection is principally involved in the regulation of lung inflammation in CF(3,4)

This project proposes to develop and optimize small molecule inhibitors of the PAF-induced NFkB pathway and distinguish compounds that are inhibiting via the toll-like receptor NFkB pathway to treat lung inflammation in CF.

REFERENCES
1. Bonfield, T.L., Konstan, M. W. & Berger, M. Altered respiratory epithelial cell cytokine production in cystic fibrosis. J Allergy Clin Immunol 104, 72-8 (1999).
2. Bonfield, T.L et al. Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. Am J Respir Cell Mol Biol 13, 257-61 (1995).
3. Zhang, Z., Louboutin, J.P., Weiner, D.J., Goldberg, J.B. & Wilson, J. M. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by toll-like receptor 5. Infect Immunol 73, 7151-60 (2005).
4. Greene, C. M. et al. TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. J. Immunol 174, 1638-46 (2005).

Please see pertinent AIDs: 588850

Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.

Grant Number: IR21 NS061743-01