1 PhD project offered in the IPP summer call 2021
This project is part of the Science of Healthy Ageing Research Programme (SHARP).
Age-related deviations of the immune system contribute to a higher likelihood of infections, cancer, and autoimmunity in the elderly. These age-related diseases share some basic mechanistic pillars that largely converge on defects especially in T cell responsiveness. While numbers and functionality of conventional CD8+ and CD4+ T cells decrease, the number of CD4+FOXP3+ regulatory T (TREG) cells seems to steadily increase during ageing. The development and function of this specialized CD4+ T cell subset with immunoregulatory properties that enforces immune tolerance and promotes tissue homeostasis relies on the transcription factor FOXP3. Yet, it is still far from being definitive how FOXP3 expression is regulated and steadily maintained and probably even enhanced during ageing in this pivotal immune regulatory cell type.
PhD project: The role of chromatin remodeling in regulatory T cells during immune ageing
Recent publications pointed to a crucial role of BAF complexes in the maintenance of TREG cell identity and function, but the detailed molecular mechanisms and their contribution in immune ageing are scarce. In this project we will focus on the molecular regulation of FOXP3 expression in TREG cells especially by BAF complex formation and function and its implication in immune ageing. To this end, we will implement conditional knock out mouse models combined with various state-of-the-art technologies, including proteomics, genomics, molecular biology, CRISPR/Cas9, flow cytometry, imaging as well as various functional assays.
We therefore seek for a highly motivated, wet-lab experienced and science-enthusiastic PhD candidate that has a strong interest in the biology of immune ageing processes as well as epigenetics. The project is highly interdisciplinary and will be performed in close collaboration between Tobias Bopp (UMC) and Sandra Schick (IMB) to combine the strength of medical and basic biological research present in Mainz.
If you are interested in this project, please select Tobias Bopp as your group preference in the IPP application platform.
Publications relevant to the project
Ulges A, Witsch EJ, Pramanik G, Klein M, Birkner K, Bühler U, Wasser B, LuessiF, Stergiou N, Dietzen S, Brühl TJ, Bohn T, Bündgen G, Kunz H, Waisman A, Schild H, Schmitt E, Zipp F, Bopp T (2016) Protein kinase CK2 governs the molecular decision between encephalitogenic TH17 cell and Treg cell development. Proc Natl Acad Sci U S A, 113:10145-50 Link
Ulges A, Klein M, Reuter S, Gerlitzki B, Hoffmann M, Grebe N, Staudt V, Stergiou N, Bohn T, Brühl TJ, Muth S, Yurugi H, Rajalingam K, Bellinghausen I, Tuettenberg A, Hahn S, Reißig S, Haben I, Zipp F, Waisman A, Probst HC, Beilhack A, Buchou T, Filhol-Cochet O, Boldyreff B, Breloer M, Jonuleit H, Schild H, Schmitt E, Bopp T (2015) Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo. Nat Immunol, 16:267-75 Link
Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity, 33:192-202 Link
Loo, Chin-San; Gatchalian, Jovylyn; Liang, Yuqiong; Leblanc, Mathias; Xie, Mingjun; Ho, Josephine et al. (2020) A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function. Immunity, 53:143-157.e8 Link
Schick S, Rendeiro AF, Runggatscher K, Ringler A, Boidol B, Hinkel M, Májek P, Vulliard L, Penz T, Parapatics K, Schmidl C, Menche J, Boehmelt G, Petronczki M, Mueller AC, Bock C and Kubicek S (2019) Systematic characterization of BAF mutations provides insights into explains intra-complex synthetic lethalities in human cancers. Nature Genetics, 51:1399–1410 Link