1-2 PhD project offered in the IPP winter call 2023/2024
Bone marrow-resident hematopoietic stem and progenitor cells (HSPC) are the source of all mature blood cells and replenish the body needs continuously in homeostasis and challenges throughout the life of the host. Although hematopoietic stem cells (HSCs) are mainly quiescent, they reversibly switch to proliferation upon challenges, such as infection, bleeding, or circadian rhythm. HSCs become dysfunctional in aging by incompletely understood cues from the bone marrow environment. This results in imbalances in the differentiation of HSPC that results in more inflammation (myeloid skewing) and age-related pathologies. Interactions of HSPC with various cellular and soluble (growth factors, extracellular vesicles) components of the bone marrow microenvironment crucially regulate the developmental fate of HSPC and proteases of the coagulation system have been shown to contribute to both matrix remodeling and regulation of homeostasis or mobilization of HSPC (extravascular coagulation signaling). Mutation or deficiencies of components of the coagulation system have been implicated in the regulation of HSPC in aging mouse models.
PhD Project: Coagulation receptors in aging
The aim of the project is to determine the contribution of extravascular coagulation and immune signaling mechanisms to unbalanced hematopoiesis in aging with a long-term goal to possibly identify rejuvenation strategies. The work of the PhD candidate(s) will include the analysis of recently identified different mouse models with accelerated aging phenotypes and apply state of the art single cell technologies to characterize HSPC phenotypes and function. Characterization of the bone marrow environment by proteomics (e.g. of extracellular vesicles) may also be required to identify underlying molecular mechanisms for altered HSPC output in aging. Theoretical and practical knowledge in molecular and cell biology and/or protein chemistry are expected for successful candidates. The candidate should have an interest in systems biology approaches and develop skills to apply bioinformatics on newly generated and available omics data sets.
If you are interested in this project, please select Ruf as your group preference in the IPP application platform.
Publications relevant to this project
Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W (2019) Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Sci Immunol 4(39). Link
Gur-Cohen S, Itkin T, Chakrabarty S, Graf C at al Ruf W and Lapidot T (2015) PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nature Medicine 21(11): 1307-1317. Link
Muller-Calleja N, Hollerbach A, Royce J, Ritter S et al Lackner KJ and Ruf W (2021) Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science 371(6534). Link
Nguyen TS, Lapidot T and Ruf W (2018) Extravascular coagulation in hematopoietic stem and progenitor cell regulation. Blood 132(2): 123-131. Link