Gene array analysis of opioid system mutant mice

Project Details

Description

DESCRIPTION (provided by applicant): Microarray profiling provides the
capability to analyze complex changes in gene expression that accompany
specific genetic and physiologic alterations. Our combined laboratories have
produced multiple mutations in the murine opioid system and have developed
technology to characterize gene expression in these models using microarrays.
We propose two aims in which opioid system KO mice will be used in gene array
studies. We will first extend preliminary data that have identified genes that
are up- and down-regulated in several opioid receptor mutants. We will identify
and characterize genes affected by opioid system disruption in the brain and
spinal cord of individual and combinatorial KO mice. Once changes in expression
have been confirmed, bioinformatic approaches will be used to determine whether
specific functional classes of genes are altered and in situ hybridization will
be used identify their cellular sites of expression. Together, these approaches
will identify specific genes whose expression is altered by opioid system
mutation, reveal the extent of compensatory change that accompanies these
mutations, either alone or in combination, and provide initial indications of
the functional significance of any changes. Second, we will explore changes in
gene expression that accompany morphine administration during the development
of analgesic tolerance and dependence to this drug using the above models. We
propose to screen acute and chronically morphine-treated wild-type, MOR-1,
KOR-1, DOR-1, ORL-l and ENK knock-out mice using microarrays to identify
morphine-regulated genes and to determine whether changes in some or all of
these morphine-regulated genes are absent in any of the above mutant strains,
which all demonstrate deficits in the development of morphine tolerance,
dependence, or both. We will extend preliminary data indicating that multiple
gene expression changes can be identified following chronic morphine exposure
and that at least some of these changes do not arise in MOR-1 mutant mice; we
expect that more restricted sets of genes may be altered in other strains, such
as DOR-1, ENK, or ORL-l KOs, in which development of analgesic tolerance
following chronic morphine treatment is either delayed or abolished. Taken
together, these studies should provide detailed, novel information about the
relationship between opioid system gene expression and that of other
neurotransmitter systems, as well as illuminate the molecular basis for
tolerance, dependence and sensitization, which are critical questions in drug
abuse research.
StatusFinished
Effective start/end date6/1/023/31/07

Funding

  • National Institute on Drug Abuse: $5,598.00
  • National Institute on Drug Abuse: $287,578.00
  • National Institute on Drug Abuse: $274,950.00
  • National Institute on Drug Abuse: $274,950.00
  • National Institute on Drug Abuse: $274,950.00

ASJC

  • Medicine(all)
  • Psychiatry and Mental health
  • Genetics
  • Neuroscience(all)

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