Non-coding genetic risk variants modulating Tregs in arthritis - Project Summary This K01 award provides Dr. Taehyeung Kim with the advanced research training, protected time, and mentoring needed to become an independent investigator specialized in functional genomics and committed to understanding the regulatory role of genetic variants conferring disease risk through Tregs. Candidate: The PI is an Instructor at Harvard Medical School in the laboratory of Dr. Peter Nigrovic in the Division of Immunology at the Boston Children’s Hospital. His previous training has provided him with extensive knowledge in the genetics of human diseases, as well as technical expertise in gene and genome editing, molecular biology, biochemistry, and manipulation of human primary immune cells. Research: Epigenetic analysis of RA GWAS variants implicates Tregs in disease risk, but how these variants affect Tregs remains largely unexplored. The PI found that the non-coding variant rs3087243 affects the immune control gene CTLA4, likely mediated by the transcription factor EGR2. Remarkably, healthy individuals carrying this risk allele have lower CTLA4 expression and fewer Tregs, potentially due to CTLA4 signaling inhibiting mTORC1. Further, we experimentally identified 197 SNPs as potential functional variants linked to RA/JIA risk via Tregs, based on allele-specific binding to Treg nuclear proteins. In Aim 1, we will investigate how rs3087243 controls Treg abundance. In Aim 2, we will uncover novel SNP-Gene-Phenotype pathways along with their regulatory mechanisms in Treg immunity, opening up the possibility of therapeutic targeting. Mentoring/Training: The PI's goal is to become an independent investigator and a tenured faculty member at a premier academic institution. The proposed research and training plan is crafted to position the PI to obtain independent R01 funding and to become an internationally recognized authority in the field of functional genomics of immune cells in autoimmune diseases. By leveraging a network of experts in his field of study, he aims to gain a deep understanding of how the human genome orchestrates cell phenotypes and the implications of dysregulation in autoimmune conditions. His research training will encompass CRISPR-based genome editing, computational biology to analyze immune cell functions through single-cell RNA-seq, and advanced techniques in immune cell phenotyping and manipulation. Additionally, he will acquire essential laboratory leadership skills to smooth the transition to his independent laboratory. This endeavor will unfold in an exceptional institutional setting, under the guidance of Dr. Nigrovic, an authority in immunology of autoimmune arthritis, Dr. Maria Gutierrez-Arcelus, an expert in functional genomics and systems biology, and an Advisory Committee comprised of Drs. Talal Chatila, a Treg biology specialist; Dr. Nir Hacohen, a luminary in molecular genomics; and Dr. Matthew Weirauch, an expert in transcription factor biology.
