International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


ORAL PRESENTATION

WEDNESDAY 12 NOVEMBER
09:45 – 10:00 HRS

THE IDENTIFICATION OF GENES CONTROLLING IMMUNE FUNCTION IN THE MOUSE BY GENOME-WIDE ENU MUTAGENESIS

Brunkow M E
Celltech R&D, Inc.

Co-Authors: 1) Staehling-Hampton K, 1) Appleby M, 2) Gilchrist J, 1) Britschgi T, 1) Charmley P, 2) Ebeling C, 1) Howard T, 2) Martin K, 1) McEuen M, 1) Paeper B, 1) Proll S, 1) Snell A, 1) Tang P, 1) Tittel P, 1) Wasnick M, 1) Wiegand N, 1) Bouck J, 1) Ramsdell F, 2) Carlson G, 1) Schatzman R
Institutions: 1) Celltech R&D, Inc., 2) McLaughlin Research Institute

We are using ENU mutagenesis in mice to identify novel, clinically relevant targets in the areas of lymphocyte biology, inflammation and autoimmunity. The approach involves a three-generation recessive screen, and we are focusing on phenotypes which mimic desired clinical responses (e.g., suppressed inflammatory response), thus improving our chances of directly identifying relevant therapeutic targets. We use a complementary set of simple in vitro assays (e.g., activation of T- and B-cells, T-dependent and T-independent inflammatory responses) as well as more complex in vivo screens which are based on classic pharmacologic models of inflammation and immune response (e.g., graft-versus-host response, air pouch and colitis). Screening has been performed both on inbred and mixed genetic backgrounds. We have developed an integrated laboratory / informatic pipeline which enables rapid identification of a candidate interval and the genes contained within, as well as efficient tracking of gene testing results, capturing both exon sequence and gene expression data. The development and utilization of informatics tools has proven critical in the effective management of the program. In the past 3 years, over 140 phenodeviants have been identified and entered into the mapping process; from these 14 causal mutations have been characterized so far. Specific lessons learned in the following areas will be discussed in more detail: 1) analyzing phenotypes on different genetic backgrounds; 2) trying to maintain and rotate a broad set of screens for interrogating as much of the immune system as possible; 3) use of point mutations for dissecting out various aspects of gene function.


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