Fine mapping and characterisation of polymorphic immunoregulatory genes in the central MHC

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/110223

Funding Status
Closed

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Funded Activity Summary

The major histocompatibility complex (MHC) is a group of genes that is usually inherited as a block. The group includes the HLA genes which can serve as markers for neighbouring genes that are less well characterised. For example, some variant forms (polymorphisms) of the HLA genes mark differences in susceptibility to diabetes, lupus and IgA deficiency. We propose that this may be caused by variations in the neighbouring uncharacterised genes affecting control of persistent inflammation of various target organs. Evidence so far suggests a gene in the central MHC may be responsible. In this project we will study DNA from patients who have unusual combinations of HLA and other MHC genes, to further define which part of the MHC contains the critical immunoregulatory genes. Most genes in the MHC have now been identified by the Human Genome Project, so we will be able to select the most promising candidates in the region of interest. We will then use DNA of known HLA types to determine if the candidate genes vary between individuals. The function of interesting genes will then be investigated by creating cell lines carrying part of the gene in the reverse (anti-sense) orientation. This generates a reverse messenger (m) RNA which binds the normal mRNA and prevents synthesis of the protein. We will then examine which responses of the resultant cell lines are abnormal (eg: production of inflammatory mediators or cytokines). Having elucidated the functions our genes, we will overexpress each version that occurs in patients in cultured cells and look for differences in function. In parallel with this work, we will use laboratory mice with known combinations of MHC genes to establish the effects of particular genes in a live animal.

Funded Activity Details

Start Date: 01-01-2000

End Date: 01-01-2002

Funding Scheme: NHMRC Project Grants

Funding Amount: $529,656.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Genetic Immunology

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

IgA deficiency | antisense technology | autoimmune disease | insulin-dependent diabetes mellitus | major histocompatibility complex | recombinant mapping | susceptibility genes | systemic lupus erythematosus

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