Deciphering the molecular basis of T1D in human cells using functional genomics

Harvard University, Cambridge MA

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Abstract

Project Abstract Type 1 Diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells of the pancreas are destroyed. These beta cells are specifically targeted for destruction by autoreactive T cells, which manage to escape the normal elimination mechanisms in the thymus. Although it is clear that besides environmental factors a strong genetic component is involved, the underlying basis for autoimmune T1D is not well understood. GWAS for a number of diseases, including T1D, have recently highlighted regulatory DNA regions rather than protein coding sequences as hot spots where single nucleotide polymorphisms (SNPs) as causal variants can be found. Our long term goal is to decipher the molecular mechanism of genotype-phenotype causalities in T1D. Our overall objective is the in depth characterization of DNA regulatory elements and their risk variants that underlie T1D susceptibility on a molecular and functional level. Our central hypothesis is that T1D associated SNPs alter the function of cell type-specific DNA regulatory elements. Guided by strong preliminary data, we will approach this hypothesis from 3 complementary angles: We will use state-of-the-art and novel computational strategies to fine map T1D GWAS SNPs to candidate causal variants (Aim 1). We will characterize the mechanism of action of causal candidates SNPs by utilizing a combination of functional genomics and proteomics (Aim 2). Finally, we will determine the functional relevance of causal variants in T1D-relevant human(-ized) systems (Aim 3). This approach is highly innovative and will provide the first in depth functional characterization of DNA regulatory elements and their risk variants that underlie T1D susceptibility. Our studies will provide a significant shift from the correlative to the functional investigation of human T1D susceptibility. Ultimately, such knowledge has the potential to translate to novel approaches to predict, prevent and potentially to treat T1D.