Life Sciences & Biotechnology
Title : | Elucidating the role of DNA methylation for pharmacoresistance in obsessive-compulsive disorder |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Epigenetics in Pharmacoresistance |
Principal Investigator : | Dr. Shabeesh Balan, Institute Of Mental Health And Neuro Sciences, Kerala |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | shabeeshbalan@gmail.com |
Details
Executive Summary : | Obsessive-compulsive disorder (OCD) is a chronic mental disorder characterized by the obsessions associated with anxiety, and in response, the individuals show compulsive behaviours for relief. OCD is highly prevalent and has a detrimental effect on the individual's functioning thus affecting the quality of life of patients and caregivers. Though dysfunction of neural circuits was shown in OCD, the underlying pathophysiology is elusive. The role of genetic and environmental risk factors is shown to contribute to the pathogenesis of OCD. The mainstay of treatment in OCD is pharmacological approaches using selective serotonin reuptake inhibitors (SSRI). Insufficient response to first-line SSRI treatment is managed by augmentation with non-selective serotonin reuptake inhibitors (SRI), clomipramine and antipsychotics. However, ~50% of the individuals fail to respond satisfactorily to any pharmacological therapy. This significantly increases morbidity, affects the quality of life, incurs an economic burden for the patients and also affects the healthcare system. Pharmacoresistance can be an inherent phenotype of OCD with underlying molecular determinants. In addition to genetic variants, epigenetic modifications stemming from environmental factors may modulate the drug response by affecting the expression of genes involved in pharmacokinetics and pharmacodynamics. Considering the role of environmental factors in OCD pathogenesis, it is imperative that the epigenetic changes can affect transcriptional regulation causal to disease pathogenesis and drug response. We posit that epigenetic changes stemming from DNA methylation signatures are distinct between drug-resistant OCD and drug-responsive OCD and the pharmacoresistance is mediated through the dysregulation of gene expression by the differential DNA methylation. Here, we aim to (i) identify differentially methylated regions between drug-resistant and drug-responsive OCD by performing genome-wide DNA methylation profiling from blood cells, which could serve as markers for predicting pharmacoresistance (ii) explore potential mechanisms of pharmacoresistance by performing pathway and gene-expression analysis of candidate genes that are differentially methylated between drug-resistant OCD and drug-responsive OCD. To the best of our knowledge, no studies to date have explored the role of DNA methylation in drug resistance/response in OCD. The results will provide differentially methylated regions in the genome that could contribute to drug resistance in OCD through dysregulation of genes/regulatory elements. By examining the gene expression pattern of top significant differentially methylated regions, the effect of DNA methylation on gene expression involved in pharmacoresistance will be validated. Taken together this pilot proof-of-principle study will provide new insights into the molecular mechanisms of pharmacoresistance and identify new candidate biomarkers for pharmacoresistance in OCD. |
Co-PI: | Dr. Rajith K Ravindren, Institute Of Mental Health And Neuro Sciences, Kozhikode, Kerala -673008 |
Total Budget (INR): | 42,07,740 |
Organizations involved