Regulation of Intestinal Innate Immunity by Speckled Protein 140

项目摘要

Project Abstract Inflammatory bowel disease (IBD) is a complex disease shaped by a combination of genetic mutations, environmental variables, the microbiome, and the epigenome. The long-term goal of the proposed research is to understand the mechanistic underpinnings of intestinal inflammation. More specifically, I seek to determine how epigenetic alterations in immune cells can promote IBD to develop novel therapeutic strategies. Our central hypothesis is that the epigenome maintains homeostatic crosstalk between immune cells and the commensal microflora. Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) within Sp140 that associate with Crohn’s disease (CD), a subset of IBD. Speckled protein 140 (Sp140) is a transcriptional regulator expressed exclusively in immune cells and contains predicted chromatin “reader” domains, including a plant homeodomain and bromodomain. Chromatin “reader” proteins dock to histone modifications where they can modulate transcription by recruiting other chromatin factors, sterically preventing transcription, or actively remodeling chromatin. Our previous work determined that Sp140 associates with closed chromatin regions in macrophages to control the transcription of lineage-inappropriate transcription factors. My preliminary data demonstrate that Sp140 regulates cytokine production in murine macrophages exposed to microbial ligands. This regulation is dependent on the presence of chromatin reader domains. However, the link between chromatin binding and cytokine regulation remains unsolved. We will delineate the mechanism by which Sp140 interacts with chromatin in macrophages and dictates macrophage effector functions. We have previously shown that CD-associated Sp140 SNPs lead to altered mRNA splicing and an overall loss of Sp140 protein. Prior published data using knockdown approaches and my preliminary data with knockout mice demonstrate that depletion of Sp140 exacerbates intestinal inflammation after epithelial barrier injury. Macrophages are sentinel innate immune cells within the intestinal lamina propria that contribute to homeostatic cytokine responses and respond to microbial invaders. We will determine the role of Sp140 in maintaining immune-microbe interactions in the intestine and preventing dysbiosis. We will also determine whether Sp140 is necessary for effective immune responses during bacteria-induced colitis. Current treatments for IBD are limited and often become ineffective in controlling relapsing intestinal inflammation. Determining the molecular and cellular mechanisms that underlie innate immune responses to microorganisms may improve IBD treatment design. These studies will inform our understanding of intestinal host immunity to pathogenic invaders and innate immune responses that promote homeostasis with commensal microbiota communities. The Research and Training Plans outlined in this application will enable me to become an innovative and effective digestive disease researcher. My Sponsor, Cosponsor, and collaborators will provide the necessary feedback and support to complete my goal of becoming an independent academic research scientist.