Gene-expression differences in peripheral blood between lithium responders and non-responders in the “Lithium Treatment -Moderate dose Use Study” (LiTMUS)
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Robert Beech
PROVIDER: E-GEOD-45484 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Analysis of gene-expression changes in treatment responders vs non-responders to two different treatments among subjectrs participating in LiTMUS. Results provide information on pathways that may be involved in the clinical response to Lithium in patients with bipolar disorder.
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Project description:Bipolar disorder is a severe and heritable psychiatric disorder and affects up to 1% of the population worldwide. Lithium is recommended as first-line treatment for the maintenance treatment of bipolar-affective disorder in current guidelines, its molecular modes of action are however poorly understood. Cell models derived from bipolar patients could prove useful to gain more insight in the molecular mechanisms of bipolar disorder and the common pharmacological treatments. As primary neuronal cell lines cannot be easily derived from patients, peripheral cell models should be evaluated in their usefulness to study pathomechanisms and the mode of action of medication as well as in regard to develop biomarkers for diagnosis and treatment response.
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Project description:Bipolar disorder (BD) (1% of the general population) is a major affective disorder characterized by recurrent manic and depressive episodes and associated with considerable burden and costs. Lithium (Li) is the first line treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, 2 years after a major episode). Li mechanism of action is rather complex and still not fully understood despite extensive studies. In order to explore potential lithium effects on global gene and miRNAs expression, we initiated a study in cell-lines from excellent responders (ER) and non-responders (NR) bipolar patients Briefly, long-term treatment response to lithium was evaluated using a validated scale “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” , also known as the Alda scale. In our sample we analyzed dichotomous phenotypes for lithium response: patients with total score (TS) higher or equal to 7, characterized as ER; and patients with TS lower than 2, characterized as NR according to the literature.
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Project description:Bipolar disorder (BD) (1% of the general population) is a major affective disorder characterized by recurrent manic and depressive episodes and associated with considerable burden and costs. Lithium (Li) is the first line treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, 2 years after a major episode). Li mechanism of action is rather complex and still not fully understood despite extensive studies. In order to explore potential lithium effects on global gene and miRNAs expression, we initiated a study in cell-lines from excellent responders (ER) and non-responders (NR) bipolar patients Briefly, long-term treatment response to lithium was evaluated using a validated scale “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” , also known as the Alda scale. In our sample we analyzed dichotomous phenotypes for lithium response: patients with total score (TS) higher or equal to 7, characterized as ER; and patients with TS lower than 2, characterized as NR according to the literature.
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Project description:Lithium has been used for more than 50 years as the primary therapy for bipolar affective disorder (BPD) and is highly effective in its treatment. However, the molecular and cellular mechanisms underlying the lithium’s therapeutic action still remains elusive. The goal of the proposed study is to identify genes involved in the lithium-responsive neurological pathway using the fruit fly as a model organism. Based on the fact that the fundamental molecular and cellular mechanisms are well conserved between the fruit fly and vertebrates, the outcomes of this project are expected to lead to the recognition of uncharacterized players or processes responsible for the lithium action in the vertebrates, which would open up the future possibility to develop novel and improved therapies for BPD. The proposed gene-profiling experiment is designed to identify candidate genes and genetic pathways involved in the lithium-responsive biological process. Specific aims of this project are; 1) identify genes whose expression levels are significantly different between the wild type and Shu, 2) identify genes whose expression levels are enhanced or suppressed after lithium treatment, and 3) identify genes whose expression is differentially regulated in the wild type and Shu after lithium treatment. We expect that the genes identified through the proposed microarray analysis will provide important clues for elucidating the molecular and cellular processes responsible for the lithium action. A Drosophila mutant Shudderer (Shu) exhibits various neurological phenotypes, including hyperactivity, uncoordinated movements, and sporadically occurring jerks. Interestingly, many of these phenotypes are greatly suppressed by lithium with the internal concentrations used for treatment of human BPD patients. In addition, Shu mutant is more resistant to the toxic effects of lithium than the wild type strain. These data have led us to the hypothesis that the biological process responsive to lithium is affected in the Shu mutant. We expect that we will be able to identify genes and genetic pathways involved in the lithium-responsive process by comparing the gene expression profiles between the wild type and the Shu mutant with or without lithium treatment. Newly eclosed Canton-S (wild type) and Shu mutant females will be placed in vials containing fly food with or without 50mM LiCl. They will be cultured at 25oC with 65% humidity for 5 days. Three groups of fifty flies (150 flies in total) will be collected for each experimental condition (i.e., genotype and lithium treatment) and frozen on dry ice. The head will be separated and total RNA will be extracted from each group using the TRIzol Reagent (Life Technologies) followed by an RNeasy (Qiagen) cleanup step and a DNase I digestion step. The RNA will be resuspended in DEPC-treated water and the absorbance will be checked at 260 and 280 nm for determination of sample purity and concentration. The GeneChip Drosophila Genome 2.0 Arrays will be used to quantify the levels of transcripts in each sample. The total number of samples will be 4 (2 genotypes and 2 treatments) X 3 (triplicate) = 12. Keywords: dose response
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Project description:Purpose: Lithium salts, used for treatment of bipolar disorder, frequently induce nephrogenic diabetes insipidus (NDI), limiting therapeutic success. NDI is associated with loss of expression of the molecular water channel, aquaporin-2, in the renal collecting duct (CD). Here, we use the methods of systems biology in a well-established rat model of lithium-induced NDI to identify signaling pathways activated at the onset of polyuria. Methods: We carried out RNA-sequencing in cortical CDs microdissected from rats treated with lithium for 12-72 hours (vs. time controls). Administration of anti-inflammatory doses of dexamethasone to lithium-treated rats countered the loss of aquaporin-2 protein. Protein mass spectrometry in microdissected cortical CDs provided corroborative evidence, but also identified decreased abundance of several anti-oxidant proteins. Cortical thick ascending limbs of Henle were also microdissected for RNA-Seq at 72 hrs. We carried out RNA-Seq for 2-3 CCD sample per rat (1 lithium-treated rat versus 1 control at 12, 24, 36 hrs). Results and conclusion: Integration of new data with prior data about lithium effects at a molecular level leads to a signaling model in which lithium increases ERK activation leading to induction of NF-κB signaling and an inflammatory-like response that represses Aqp2 gene transcription.
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