A multi-organ approach to investigate the endothelium during vascular and neuronal aging and inflammation (EndoAge)
3 PhD projects offered in the IPP summer call Molecular Biomedicine & Ageing
Scientific Background
Endothelial cells line the inner layer of all blood vessels and play a key role in vascular and organ homeostasis. Endothelial cells also provide important barriers and have the ability to selectively prevent or to allow the transmigration of cells, but also the endocytosis of molecules and their transcytosis into the subendothelial space. Our central hypothesis is that inflammation and aging impact on the protective role of endothelial cells in an organ-specific manner and that the endothelium represents an ideal therapeutic target to prevent detrimental vascular aging and disease progression. To address this hypothesis, our combined research efforts will examine endothelial-driven mechanisms of vascular inflammation and their role for selected age-associated disease processes in the nervous and cardiovascular system, such as Alzheimer’s disease, multiple sclerosis, atherosclerosis and heart failure. We will also analyze in which way systemic and local immune and inflammatory stimuli, circulating proteins in the blood stream, or bacterial compounds from the gut influence the endothelium in different vascular organ beds. Mechanistically, we will focus on the organ-specific roles of endothelial cells and mechanisms providing selective barriers, influencing endothelial endocytosis, and controlling proteostasis, and how these mechanisms can be specifically targeted to prevent endothelial aging and inflammation. We will divide our research efforts into the following main project areas:
PhD Project 1: Organ-specific and systemic mechanisms of endothelial barrier function and dysfunction 1,2
If you are interested in this project, please select Wenzel/Waisman (Mech) your group preference in the IPP application platform.
PhD Project 2: Metabolic, bacterial and inflammatory modulators of the endothelial barrier 3,4
If you are interested in this project, please select Wenzel/Waisman (Mod) your group preference in the IPP application platform.
PhD Project 3: Therapeutic targeting of the endothelial barrier to prevent aging and inflammation 5,6
If you are interested in this project, please select Wenzel/Waisman (Ther) your group preference in the IPP application platform.
Within these project areas, and in a collaborative effort, the consortium will examine the following specific aims:
To understand the causal role of changes in endothelial cell metabolism and endocytosis receptor expression for vascular disease processes;
To examine how the gut microbiome impacts on local (intestinal) and distant (brain, liver, heart) endothelial cell barriers to promote organ inflammation and degeneration;
To study how systemic inflammation induces endothelial barrier disruption and neuronal impairment; and
To assess whether age-associated changes in endothelial cells are amenable to specific therapeutic targeting and drug delivery to prevent or to halt vascular inflammation, remodeling and degeneration.
In this Core Team of our consortium EndoAge, each PhD student will be co-supervised by two PIs, paired from cross-disciplinary areas in translational research and medicine.
Publications relevant to these projects
1. Johann L, Soldati S, Muller K, Lampe J, Marini F, Klein M, Schramm E, Ries N, Schelmbauer C, Palagi I, et al. (2023) A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS. J Clin Invest. 133. doi: 10.1172/JCI168314 Link
2. Storck SE, Meister S, Nahrath J, Meissner JN, Schubert N, Di Spiezio A, Baches S, Vandenbroucke RE, Bouter Y, Prikulis I, et al. (2016) Endothelial LRP1 transports amyloid-beta(1-42) across the blood-brain barrier. J Clin Invest. 126:123-136. doi: 10.1172/JCI81108 Link
3. Guilherme MDS, Nguyen VTT, Reinhardt C, Endres K. (2021) Impact of Gut Microbiome Manipulation in 5xFAD Mice on Alzheimer's Disease-Like Pathology. Microorganisms. Apr 13;9(4):815. doi: 10.3390/microorganisms9040815 Link
4. Bochenek ML, Saar K, Nazari-Jahantigh M, Gogiraju R, Wiedenroth CB, Munzel T, Mayer E, Fink L, Schober A, Hubner N, et al. (2024) Endothelial Overexpression of TGF-beta-Induced Protein Impairs Venous Thrombus Resolution: Possible Role in CTEPH. JACC Basic Transl Sci. 9:100-116. doi: 10.1016/j.jacbts.2023.08.005 Link
5. Zanetti C, Kumar R, Ender J, Godavarthy PS, Hartmann M, Hey J, Breuer K, Weissenberger ES, Minciacchi VR, Karantanou C, et al. (2021) The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13. Blood. 138:1870-1884. doi: 10.1182/blood.2021011557 Link
6. Garlapati V, Molitor M, Michna T, Harms GS, Finger S, Jung R, Lagrange J, Efentakis P, Wild J, Knorr M, et al. (2023) Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-beta1-driven fibrotic remodeling in ischemic heart failure. J Clin Invest. Feb 15;133(4):e156436. doi: 10.1172/JCI156436 Link