Project Details
Projekt
Deciphering the role of Cyclin-T1 in human immune cell plasticity – Insights from children with inflammatory bowel disease (A05)
Subject Area
Gastroenterology
Term
from 2013 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 210592381
Our genetic analysis of the largest international very early onset inflammatory bowel disease (VEO-IBD) cohort has unraveled deficiency in Cyclin-T1, a major regulatory subunit of the cyclin-dependent kinase 9 (CDK9) that controls transcriptional elongation, as a novel genetic entity in three unrelated families. Here, we propose to decipher the mechanisms of immune dysregulation and inflammation in patient-derived or CRISPR/Cas9-engineered naïve T cells as well as in Cyclin-T1-deficient macrophages or in humanized mice reconstituted with patient-derived or CRISPR/Cas9-engineered hematopoietic progenitor or immune cells. In these systems, we will analyze the differentiation and activation, signal transduction, as well as cytokine and chemokine profiles of immune cell subpopulations in lymphoid and intestinal tissues by high-dimensional immunophenotyping and transcriptional profiling, and monitor the development of spontaneous or chemically-induced colitis. We postulate that our studies on monogenic VEO-IBD will provide mechanistic insights into the role of Cyclin T1 in human immune cell plasticity, help to predict effects and toxicities of therapies targeting CDK9, and facilitate the discovery of biomarkers and therapeutic targets for rare and common immune disorders.
DFG Programme
Collaborative Research Centres
Applicant Institution
Ludwig-Maximilians-Universität München
Project Heads
Professor Dr. Christoph Klein, until 12/2020; Professor Dr. Daniel Kotlarz, since 1/2017
