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Research project (§ 26 & § 27)
Duration : 2018-07-01 - 2021-06-30

Clinical and historical data underscore the ability of influenza viruses to ally with certain bacterial species and predispose the host for secondary bacterial infection. Bacterial pneumonia postinfluenza infection was identified as the major cause of mortality during the most devastating influenza pandemics in 1918/19 and 1957/58 with S.aureus and S.pneumoniae being the most commonly associated etiological agents. Vaccination is the best method to prevent infectious disease. There is, however, no S.aureus prophylaxis available and S.pneumoniae vaccines were shown to be largely ineffective. On top, the rise of multi-drug-resistant bacterial strains is alarming. Yet, it was shown that by limiting primary viral infection, influenza vaccines are able to decrease subsequent secondary bacterial infections, leaving influenza vaccines as only promising measure to prevent secondary bacterial complications. Low cross-reactivity of current influenza vaccines, however, still enables drifted influenza strains to cause disease and may prime patients for difficult-to-treat bacterial superinfections. Several viral and host key players have been identified to increase susceptibility of the host for postinfluenza secondary infection. The influenza neuraminidase was shown to increase bacterial adherence to epithelial tissues, by unmasking and up-regulating expression of cellular receptors. The viral proteins PB1-F2 and NS1 may suppress the host innate bacterial responses by modulating the host interferon response and dysregulating cytokine and chemokine secretion. Current influenza vaccines are standardized as per their hemagglutinin content and the amount of other viral proteins present is predefined by their natural abundance in the influenza virion. This leaves the influenza NA and (to an even higher degree) the NS1 largely underrepresented in current vaccines, whereas PB1-F2 is even absent. We aim to supplement/enrich a virus-like particle preparation based on the influenza HA and a non-influenza capsid protein with these antigens at different ratios compared to the HA. These preparations will be evaluated for their beneficial contribution in protective efficacy against S.aureus and S.pneumoniae infections after heterologous influenza infection; mimicking the situation of vaccine mismatch.
Research project (§ 26 & § 27)
Duration : 2018-05-01 - 2021-04-30

We found previously that lack of a specific m5C methylation on 28S ribosomal RNA conferred by Nsun5 leads to increased lifespan and stress resistance of yeast, worms and flies. However, if Nsun5 or any other RNA methyltransferase is also capable of modulating healthy lifespan of mammals is not known. Thus, the aims of this project encompass the measurement of the lifespan of a Nsun5 constitutive whole-body knockout mouse model compared to littermate controls, as well as phenotypic evaluation of health that we hypothesize to be improved by Nsun5 knockout at advanced age. Mice of both sexes in a C57BL6/J background will be tested. We further hypothesize that loss of Nsun5 also increases stress resistance on cellular level and alters ribosome function. This hypothesis will be tested by characterization of Nsun5 activity in different tissues and at different timepoints during the lifespan, assessment of cellular fitness by measurement of stress resistance in-vitro, as well as translation rate and fidelity. We will further isolate mRNAs contained in ribosomes by immunoprecipitation utilizing the ribo-tag platform, and compare their expression to total cellular mRNAs. Thereby we will be able to identify global gene expression patterns of translational regulation and confirm the presence of similar regulatory elements as we found in yeast, such as upstream open reading frames. Due to the high evolutionary conservation of Nsun5, we are convinced that conclusions obtained within this project are also applicable to humans. Thus, the experiments proposed here will contribute to a better understanding of the contribution of ribosomal RNA methylation to organismal fitness and probably pave the ground for the design of healthspan extending strategies in humans.
Research project (§ 26 & § 27)
Duration : 2017-03-01 - 2020-02-29

The proposed project is designed to test the hypotheses that successful cartilage regeneration requires the recapitulation of embryogenic processes and that the secretome of fetal cells can initiate fetal-like regeneration of cartilage. Osteoarthritis (OA), a degenerative joint disease characterized by progressive articular cartilage degeneration, is one of the leading causes of disability worldwide and is associated with a tremendous individual and socioeconomic burden. Adult articular cartilage (AAC) has limited intrinsic repair capacity and current medical treatment options provide only symptomatic relief without significantly altering the disease progression or restoring cartilage integrity. Therefore, injured cartilage does not regenerate but forms fibrocartilaginous repair tissue with impaired biomechanical properties which does not adequately substitute for hyaline cartilage, thereby precipitating the continuation of joint inflammation leading to chronic osteoarthritis. In contrast to AAC, fetal articular cartilage (FAC) subjected to partial thickness lesions fully regenerates. In addition, fetal cells transplanted into an adult organism have been shown to retain their regenerative potential in skin, liver, tendon and cartilage models. Information on regenerative healing in fetal animals may allow improvement of the healing response in mature tissue. The cell secretome has a key role in tissue regeneration but is poorly understood. An improved knowledge of the factors involved in healing is a key prerequisite for utilizing this potentially powerful tool for therapeutic applications. We intend to develop a novel, biomimetic treatment strategy, recapitulating aspects of fetal articular cartilage morphogenesis to achieve fetal-like regeneration of adult articular cartilage. We propose to carry out a comprehensive study comparing 1) fetal (gestational day 80, term ~ 145 days of gestation) and adult cartilage healing in vivo 2) the effect of fetal chondrocytes, fetal mesenchymal stem cells (fMSCs), adult chondrocytes and adult bone marrow derived mesenchymal stem cells (aMSCs) and the secretome of these 4 cell types on adult articular chondrocyte proliferation, chondrogenic matrix production, and gene expression in vitro and 3) to identify key factors responsible for the induction of fetal healing rather than adult repair. The achieved knowledge will lead to further developmental work following up the proposed project, in order to establish an economically exploitable therapy approach, which will induce fetal healing in adult cartilage. The novel therapy will give the company partner involved in this project a competitive edge in this field at an international level.

Supervised Theses and Dissertations