Project E: Isolation of Novel Transcripts &Proteins in Hypocretin-Containing Cells The etiology of narcolepsy-cataplexy is now known to involve a degeneration of hypocretin-containing neurons in the hypothalamus. The cause of the hypocretin cell loss is unknown but, considering the well known HLA-narcolepsy association, likely to be autoimmune. Preliminary studies have not identified any specific autoantibodies against hypocretin peptides themselves, suggesting the existence of other factors Simple western blots and immunochemical staining experiments have also failed to reveal evidence fo hypothalamic-directed autoimmunity. Novel experimental approaches are needed to identify additiona factors. The goal of our revised proposal is to systematically isolate and study genes and gene products preferentially expressed in hypocretin-producing neurons. We believe that the identification of these factors will further our understanding of the physiology of these cells and provide further candidate proteins for the presumed autoimmune origin of narcolepsy. To isolate and study these factors, we will (1) Use gene expression array studies in hypocretin neuron deficient versus wild-type littermate mouse brains to establish a collection of transcripts potentially expressed specifically in hypocretin neurons. Hypocretin knockout mice will be used as an additional control. (2) Use subtractive hybridization to generate a collection of low abundant transcripts enriched in mouse hypocretin neurons. (3) Use gene expression arrays and quantitative mmunohistochemistry with brain tissue obtained from narcoleptic patients with and without cataplexy and com control individuals to establish key differences among these groups. (4) Validate all possible ranscriptional candidates by quantitative real time (RT)-PCR and in situ hybridization and explore their nvolvement in the pathophysiology of narcolepsy. This will involve verification of primary expression in hypocretin cells and basic characterization of diurnal variation. Depending on the candidate genes, other ypes of functional validation such as immunological studies, generation of genetically modified animals or candidate gene analysis in human narcolepsy DMA samples may be carried out. Whether or not narcolepsy s an autoimmune disease, the identification of products specific for hypocretin-containing cells is likely to shed new light into the pathophysiology of narcolepsy. These studies are the logical next step toward understanding why hypocretin cell loss occurs in human narcolepsy.
| Bonvalet, Melodie; Ollila, Hanna M; Ambati, Aditya et al. (2017) Autoimmunity in narcolepsy. Curr Opin Pulm Med 23:522-529 |
| Plante, David T; Finn, Laurel A; Hagen, Erika W et al. (2016) Subjective and Objective Measures of Hypersomnolence Demonstrate Divergent Associations with Depression among Participants in the Wisconsin Sleep Cohort Study. J Clin Sleep Med 12:571-8 |
| Gottlieb, D J; Hek, K; Chen, T-H et al. (2015) Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Mol Psychiatry 20:1232-9 |
| Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang et al. (2015) HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 96:136-46 |
| Li, Jason; Moore 4th, Hyatt; Lin, Ling et al. (2015) Association of low ferritin with PLM in the Wisconsin Sleep Cohort. Sleep Med 16:1413-1418 |
| Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine et al. (2015) Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun 49:54-8 |
| Kawai, Makoto; O'Hara, Ruth; Einen, Mali et al. (2015) Narcolepsy in African Americans. Sleep 38:1673-81 |
| Holm, Anja; Lin, Ling; Faraco, Juliette et al. (2015) EIF3G is associated with narcolepsy across ethnicities. Eur J Hum Genet 23:1573-80 |
| Jacob, Louis; Leib, Ryan; Ollila, Hanna M et al. (2015) Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain Behav Immun 47:44-57 |
| de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78 |
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