T1D is an autoimmune disease in which cytotoxic T cells attack and destroy insulin-secreting pancreatic beta cells. The role of genetics in T1D development is evident from its clustering in families. Although genome-wide association studies uncovered the T1D-associated single-nucleotide-polymorphisms, currently there is a large gap in knowledge regarding the molecular processes through which genetics contributes to autoimmunity. Specifically, because most disease-associated SNPs have been found in non-coding genomic regions, they are thought to impact gene regulation rather than causing production of mutated proteins. Recent advances in our understanding of nuclear organization indicate that genetic variation may impact gene regulation through altered 3D genomic structure and reorganization of large transcriptionally coordinated regions of the genome in the disease relevant cell type(s). However, the link between sequence variation, cellular context, 3D genome organization, and aberrant gene expression in T1D remains largely unknown. Our overall objective is to define the molecular hallmark of T1D-associated immune cells from human pancreatic tissues and study the utility of such deep profiling in detecting early T1D processes. Our latest results provide the first-ever evidence of early transcriptomics and 3D epigenomic alterations in T1D. Our hypothesis is that pathogenic immune cell subtypes residing in pancreatic tissues in asymptomatic and clinically diagnosed phases of T1D share transcriptional and 3D epigenomic signatures. We propose to generate the deepest-possible molecular profiling of immune cell populations in pancreatic tissues and peripheral blood in clinically well-characterized human organ donors collected by HPAP. Since the most accessible entity for biomarker testing, i.e. blood, is the conduit by which major immunological traffic occurs, we will examine if immunological features of beta cell destruction can be found in peripheral blood at asymptomatic stages of T1D. Once the molecule and epigenomic signatures of T1D are precisely defined in pancreatic tissues, they can be used as a powerful magnet to look for the needle in the haystack of circulating cells. Our single-cell resolution experiments will identify T1D-associated immune cells and deregulated genes in pancreatic tissues (Aim 1). Our state-of-the-art epigenomics, imaging, and genome engineering techniques will determine 3D genome misfolding events associated with T1D (Aim 2). The outcomes of each Aim can dramatically expand our understanding of early disease processes. The integration of knowledge gained in two Aims can elucidate detailed molecular mechanisms of pathogenic gene regulation in T1D.
Type 1 diabetes (T1D) is a chronic autoimmune disease where cytotoxic T cells destroy insulin-producing beta cells. Although genome-wide association studies uncovered the T1D-associated single-nucleotide- polymorphisms, the molecular processes through which sequence variation leads to autoimmunity remains unclear. Our overall objective is to define the molecular hallmark of T1D-associated immune cells from human pancreatic tissues and study the utility of such deep profiling in detecting early T1D processes.
