We will investigate whether human endotoxemia induces changes in human bone marrow cells and their downstream effector cells. To comprehensively investigate underlying mechanisms behind functional and transcriptional changes in these cell types, we will use state-of-the-art systems biology techniques, including single cell transcriptomics (epi)genetics, and metabolomics.
In the present study, we want to further elucidate the mechanisms behind systemic inflammation and endotoxin tolerance in vivo in humans by focusing on functional changes in hematopoietic stem and progenitor cells. Healthy male volunteers will be challenged with endotoxin to evoke a transient systemic inflammatory response. To evaluate the responses over time, blood and bone marrow aspirates will be collected at multiple timepoints. To comprehensively investigate underlying mechanisms behind functional changes, we will use state-of-the-art systems biology techniques, including single cell transcriptomics, epigenetics (e..g. scATACseq), and metabolomic. As such, this study will yield a comprehensive insight into inflammatory signaling in the different compartments of the body and will thereby improve our understanding of systemic inflammation, endotoxin tolerance,and sepsis, possibly revealing new therapeutic targets to improve sepsis outcome.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
12
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands
Change in function and transcriptional pathways
The change in function and transcriptional pathways (gene expression) of hematopoietic progenitor cells and blood leukocytes (using various functional assays and single cell RNAseq) following human endotoxemia.
Time frame: 15 days
Change in (Genome-wide) chromatin accessibility
The change in epigenomic profile (chromatin accessibility) of hematopoietic progenitor cells and blood leukocytes (using single cell ATACseq) following human endotoxemia.
Time frame: 15 days
Change in cellular metabolism
The change in cellular metabolism of hematopoietic progenitor cells and blood leukocytes (e.g. using Seahorse analyzer, CYTOF) following human endotoxemia.
Time frame: 15 days
Change in macrophage activity in the brain
To changes in tissue resident macrophages activity in the brain (assessed using 18F-DPA-714 labeling and PET examinations) following human endotoxemia.
Time frame: 15 days
Life-span of blood leukocytes during homeostasis
To assessment of the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans at homeostasis (using Deuterium labeling).
Time frame: 8 days
Life-span of blood leukocytes during endotoxemia
To determine the life-span and transit times of different subsets of leukocytes and their progenitors in the bone marrow of humans during human endotoxemia (using Deuterium labeling).
Time frame: 8 days
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.