Restless legs syndrome (RLS) is a chronic sleep motor disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move them for relief. Past pathophysiological studies have associated RLS to the disorder of the central dopaminergic system and iron metabolism. Family and twin studies strongly support a genetic contribution to the pathogenesis of RLS. Tremendous progress has been made recently of uncovering candidate genes linked to RLS. Three independent studies published in the last two years all pointed to the role of BTBD9 in RLS. The function of BTBD9 protein is not known. Current animal models include 6-hydroxydopamine-lesioned rodents, iron deficiency mice, and dopamine receptor 3 knockout mice. The identification of the RLS candidate genes paves the way for making genotypic model of RLS that will be more relevant in elucidating the pathophysiology of RLS and developing therapeutic treatments. The broad, long- term objective of our research is to use transgenic mice to determine: 1) the functional role of BTBD9 protein in vivo, 2) how the alteration of BTBD9 protein function could lead to RLS. The objective of this application is to characterize Btbd9 (mouse homolog of the human BTBD9 gene) knockout mice we have already made that will enable us to answer these questions. We hypothesize that BTBD9 mutations lead to alteration of brain iron metabolism and central dopaminergic system especially the striatal D2 receptor mediated indirect pathway, or diencephalic-spinal dopaminergic tracts (A11), or both. This in turn leads to enhanced unpleasant sensations, circadian dysfunction, and strong urge to move. We plan to test our hypothesis with the following Specific Aims: 1. To test the hypothesis that BTBD9 mutation disrupts dopaminergic function, we will measure animal's response to amphetamine administration in open field apparatus and examine the morphology and number of A11 neurons in hypothalamus that are known to project to spinal cord. Levels of tissue dopamine, their metabolites, and dopamine receptors will also be determined in striatum. 2. To test the hypothesis that BTBD9 mutation leads to the strong urge to move and hyperactivity, we will monitor animals'activity in home cages over several days. In addition, the mutant mice will be tested in cages with free access running wheels that are ported to a computer. These experiments will reveal whether mutant Btbd9 mice show any circadian variation of motor activity. 3. To test the hypothesis that BTBD9 mutation affects iron metabolism, we will measure striatal and nigral ferritin, transferrin and total iron in the Btbd9 mutant mice. 4. To test the hypothesis that BTBD9 mutation affects sensory system, we will measure the pain threshold using tail flick and hot plate assays, and sense of touch using Von Frey fibers. The successful completion of the above Specific Aims will help us to determine the function of BTBD9 protein in vivo and how the mutation of BTBD9 causes RLS. The results should significantly increase our understanding of the pathophysiology of RLS, which can ultimately aid the development of therapeutic treatments for RLS patients.
The successful completion of the proposed research project will help us to determine the function of BTBD9 protein and how the mutation of BTBD9 gene causes Restless Legs Syndrome. The results should ultimately aid the development of therapeutic treatments for Restless Legs Syndrome patients.
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