New therapeutic targets in immune disorders: ItpkB, Orai1 and UNC93B

Abstract

Background: Sequencing of the murine and human genomes has enabled large-scale functional genomics approaches to target identification. This holds the promise of drastically accelerating target discovery. Moreover, by providing an initial validation coincident with target identification, cell based cDNA or small interfering RNA (siRNA) screens and in particular genome-wide in vivo approaches, including forward or reverse genetics and analyses of natural gene polymorphisms, can move the relatively late step of target validation to the beginning of the process, reducing the risk of pursuing targets with little in vivo relevance. Objective: We critically discuss the value of combining functional genomics with traditional approaches for accelerating target identification and validation. Methods: We evaluate the potentials of inositol (1,4,5)trisphosphate 3-kinase B (ItpkB), Orai1 and UNC93B, three particularly interesting proteins that were recently identified through functional genomics, as targets in immune disorders. Results/conclusion: Combining functional genomics with traditional approaches can accelerate target discovery and validation, but requires a follow-up platform that integrates and analyzes all relevant data for assessment of the clinical potential of the growing number of novel targets.

Keywords::

• anti-inflammatory
• autoimmune disease
• BTP2
• CRAC
• CRACM1
• dendritic cell
• ethylnitrosourea ENU mutagenesis
• forward genetics
• functional genomics
• haplotype
• immune suppression
• inositol
• IP3KB
• IP₄
• ItpkB
• macrophage
• Orai1
• phosphoinositide
• reverse genetics
• SCID (severe combined immune deficiency)
• Stim1
• T cell
• TLR
• transplant rejection
• UNC93B

Acknowledgements

We thank Su Li for critical reading of the manuscript and our lab members for valuable discussions.

Notes