Research projects

Polytarget project A02 deals with the development and testing of Polysaccharide-based nanoparticles as drug carriers. Polysaccharides are well suited polymers for medical application as they are non-toxic, biocompatible, biodegradable and their structure can be widely modified.  Our nanoparticles are loaded with histone deacetylase inhibitors (HDACi). They act on the acetylation of histones and non-histone proteins thereby influencing various cellular processes through altered signaling and gene expression. HDACi show anti-inflammatory properties and could be beneficial in the treatment of inflammation and sepsis. Since the free drugs have a short serum half life time and side effects, binding to nanoparticles could overcome these drawbacks and lead to a controlled release.

Our group evaluates the effects of HDACi-loaded nanoparticles in the biological system. We are assessing the cellular uptake, localization and fate, biological activity and biocompatibility in cell lines, primary immune cells, organoids and the model organism C. elegans.

In collaboration with working group BrakhageExternal link (Leibniz Institute for Natural Product Research and Infection Biology), we are investigating the specific interaction between the filamentous fungus Aspergillus nidulans and the soil bacterium Streptomyces rapamycinicus in project B02 of ChemBioSys. As a result of the interaction, the chromatin structure in the fungus changes and the cryptic orsellic acid cluster is induced. Our work focuses on the investigation of the involved transcription factors, histone acetyltransferases (HATs), and histone deacetylases (HDACs) leading to epigenetic changes in the fungus.

Cell state transitions are per se alterations in the molecular identity – or “phenotype” - of a cell to fulfill different functions. Since somatic cells and diploid germ cells share the same genome, an additional layer of information must exist to create phenotype diversity. The so-called epigenome comprises the sum of biochemical information that is attached to the DNA or DNA packaging histones without altering the genetic code itself. Interestingly, our epigenome is highly dynamic and epigenetic information might be transmitted via germ cells over generations. 

We wish to understand how epigenetic modifiers and transcription factors maintain a distinct cellular state or induce a molecular transition in normal development, pathogenesis or aging.

Stress induces persistent and functional epigenetic changes, affecting health and lifespan. The hypothalamus-pituitary-adrenal (HPA) axis is the major neuroendocrine circuit that initiates and regulates adaptation to stress, thus promoting survival. Upon encountering stressors, such as an immune challenge, the HPA axis triggers the release of glucocorticoids (GCs) such as cortisol. Cortisol binds to the glucocorticoid receptor (GR) in target cells and activates an anti-inflammatory transcriptional response to mitigate the threat and restore homeostasis. Therefore, low levels of acute stress bolster resilience. During aging, senescent cells that exhibit a pro-inflammatory secretory phenotype (SASP) accumulate and fuel a chronic, systemic, low-grade inflammatory state termed inflammaging. This state accelerates age-related comorbidities such as frailty, neurodegenerative and cardiovascular diseases.

How aging-associated deregulation of the HPA axis and GC-GR signaling impact inflammaging remains unclear. Moreover, GR modulates the chromatin landscape in the vicinity of the DNA methylation sites, linking stress response to epigenetic age. In this study, we will investigate the relationship between epigenetic age, cortisol and pro-inflammatory cytokine levels, and GR expression in aging human cohorts. Using cell culture and animal models, the molecular mechanisms underlying GR-mediated epigenetic regulation of senescence and inflammaging will be interrogated. Moreover, we will address whether anti-inflammatory interventions employing synthetic glucocorticoids can be used as senomodulators to suppress SASP and improve healthspan in model organisms.

Funding as part of the university's "IMPULSE - Project" program:

Regulation of hepatic immune response and metabolism by glucocorticoids

The glucocorticoid receptor (GR) is a ubiquitously expressed, ligand-activated transcription factor. Cellular effects of the hormone cortisol, or other synthetic glucocorticoids (GC) such as dexamethasone, are mediated by GR.  GR-dependent gene expression programs are involved in the regulation of stress, inflammation and metabolism. The role of synthetic GCs as anti-inflammatory agents in the treatment of rheumatoid arthritis, asthma and COVID-19 are well-established. However, chronic exposure to high levels of GCs has deleterious repercussions and can contribute to the development of metabolic disorders.

The liver is not only the major metabolic organ but also a key innate immune mediator of the body. We are interested in understanding the impact of GCs on the inflammatory response in hepatocytes and the consequential metabolic outcome. To this end, we use human cell lines to perform transcriptomic, proteomic, and epigenetic assays to decipher GR-dependent hepatic gene programs. We combine genetic engineering by CRISPR/Cas9, lentiviral transductions and DNA transfections with RNA-sequencing, APEX2-mediated proximity labeling, chromatin immunoprecipitation and chromatin accessibility assays to understand the impact of GC-GR signaling.

Also see here:
https://www.uni-jena.de/en/all-news/acetylation-a-time-keeper-of-glucocorticoid-sensitivity