Opioid Receptor Polymorphism &PD Drug Response

Project Details

Description

DESCRIPTION: (Verbatim from the Applicant's Abstract) Parkinson's disease (PD)
is a common movement disorder with tremor, rigidity, and bradykinesia. The
central event in PD is the loss of the dopaminergic inputs to the basal
ganglia. The disease is characterized by great variability from patient to
patient in the course of the disease, the relative predominance of various
symptoms, the response to L-DOPA therapy, and the development of dyskinesias
during L-DOPA therapy. Studies exploring the ramifications of the dopamine
deficiency in PD have provided increasing evidence that changes in the other
basal ganglia neurotransmitter systems, in particular the opioid system, may
also play a role in the disease process. This evidence includes PET scan
studies in PD patients that showed correlations between dyskinesias and altered
opioid binding levels, as well as work in animal models sugggesting the
involvement of opioid system in the development of dyskinesias during L-DOPA
therapy.

In this revised application, the basic hypothesis we propose to test is that
some of the observed variability in PD patient's symptoms and response to
L-DOPA may be related to an underlying genetic variation in opioid receptors.
We propose to study genetic polymorphism of the mu opioid receptor in PD
patients, and to characterize at a cellular level the consequences of these
polymorphisms on receptor expression level and receptor function. The specific
aims of the proposal are: 1. To identify genetic polymorphisms in both the
promoter and the coding region of the mu opioid receptor in PD patients and to
determine whether any of the polymorphisms are associated with variations in
clinical symptoms and outcomes: 2.) To determine the effect of the coding
region polymorphisms on both ligand binding properties of the receptor and
receptor-mediated cellular functions; and 3.) To determine the effect of
promoter sequence polymorphisms on the expression levels of the receptor. Such
functional studies are essential in moving from association to causality.

Our preliminary studies of 26 PD patients have identified a mu opioid receptor
polymorphism in the PD population. This polymorphism was significantly
associated with the clinical outcome of L-DOPA therapy-induced dyskinesia.
Further studies in a larger PD patient cohort may identify additional
polymorphisms of interest, and may provide predictor for clinical management of
PD.
StatusFinished
Effective start/end date5/1/012/27/08

ASJC

  • Clinical Neurology
  • Neurology

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