Research Projects

Inflammatory Bowel disease (IBD), comprising of Crohn’s disease (CD) and ulcerative colitis (UC) results from a complex interplay of genetic, immunologic and microbial factors. Human circulating monocytes enter the intestinal lamina propria and regulate cytokine production in the mucosa and dictate the outcome of IBD. Genome wide association studies (GWAS) have led to identification of multiple loci that makes one susceptible to IBD and a number of genes have been shown to regulate cytokine production or antibacterial killing, autophagy etc. However, of the 200 loci associated with IBD, functional consequences of the majority of these loci have yet to be identified. We have been working to understand the association of multiple SNPs associated with IBD and determine causal variants (Khan and Lahiri, JCI Insight, In revision). We initiated the current study to delineate the functional aspect of rs24488389 (non-coding SNP in chromosome 1, G to A, AA risk allele), an IBD associated variant and observed that the blood derived monocytes from AA risk careers produced higher cytokine that the GG haplotypes. We have strong preliminary data that this functional polymorphism regulates expression of only one uncharacterized small open reading frame, C1orf53 (Chromosome-1 open reading frame 53) in this loci. We observed that C1orf53 is localized to mitochondria and regulate bacterial ligand induced cytokine secretion from human monocytes and over-expressed in human UC patients. Immune-mediated diseases, like IBD exhibit dysregulated cytokines in the intestine. We, therefore, hypothesize that C1orf53 is a crucial regulator of immune function and dictate IBD susceptibility in the individuals. Function of C1orf53 is unknown, and we will focus to gain insight about the function of this gene in both animal model and human IBD patients. The major goal of this study is to functionally dissect the consequences of disease‐associated genetic variation at rs24488389 locus in order to correctly attribute an association with a gene. Collectively, our findings have begun to shed light on these questions and if funded, will provide a rich source of clues to the pathogenic mechanisms C1orf53 plays in immune function, specifically during IBD. We will work closely with our clinician collaborators Prof. Tulika Chandra (KGMU, Lucknow) and Prof. Uday C Ghoshal (SGPGI, Lucknow). We will specifically explore how C1orf53 regulates immune outcome in human primary monocytes and unravel the function it operates in the mitochondria. The mechanistic studies will next be performed in the animal model of colitis to exactly know how C1orf53 can dictate IBD susceptibility with our co-investigator Dr. Manoj Barthwal. Collectively, identifying the genetic contribution of this locus, specifically how C1orf53 makes one susceptible to IBD will decipher multiple important aspects of disease biology, such as prognosis and marker identification.