Project: Research project

Project Details


Genetic factors contribute to the expression of autoimmune diseases in
both mice and humans. These genes are largely uncharacterized; moreover,
their gene products and mechanisms of action are unknown. A recessive
mutation, lpr, that occurred in MRL mice results in profound
lymphadenopathy with expansion of an unusual subpopulation of T cells and
generalized autoimmune disease. A "reverse" genetic approach is proposed
to identify the mutant or deficient gene products of the lpr locus and
MRL genes that interact with lpr to result in renal disease. The method
relies on defining the physical location of these genes. RFLV and
microsatellite polymorphisms will be used as markers in two different
crosses segregating for the recessive genes that are critical to clinical
and serologic disease in these mice. The renal histology will be scored
and correlated with the genotype analyses and autoantibody profiles. The
localization of lpr to mouse Chr 19 will be confirmed and saturation
mapping using clones from a flow sorted mouse Chr 19 library will be
performed. Of most interest will be defining the MRL quantitative trait
loci (QTL) that predispose to nephritis. Detailed mapping of each
relevant region of the genome will be undertaken using available clones
localized to the specific chromosome segment and clones likely to be in
that region of the genome. If necessary, a subchromosome specific
library or a chromosome microdissection library will be generated to
allow saturation mapping of one of the identified QTL regions. Long
range restriction site analyses of the relevant regions of the mouse
genome will be performed. If, as is likely, one or more autoimmune loci
are within a chromosomal segment largely conserved between the mouse and
human genome, these studies may identify the chromosomal location of
human "autoimmune genes". A variety of strategies including the use of
chromosome jumping and a mouse yeast artificial chromosome library, in
addition to long range restriction mapping will be used to more precisely
define the molecular location of the critical gene (s) responsible for
genetic predisposition. Comparison with MRL-plus-minus/plus-minus mice
will be useful for determining the lpr mutation as will comparison of
CBA/KJ with a new mutation at the lpr locus in a strain designated
CBA/KJ-lpr(cg) . For other localized "autoimmune genes", candidate genes
may be suggested by their chromosomal location. Definition of a single
gene that predisposes to autoimmunity should allow fundamental insight
into molecular basis for disease in mice and humans.
Effective start/end date9/30/928/31/97


  • National Institutes of Health: $251,657.00
  • National Institutes of Health
  • National Institutes of Health: $207,109.00
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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