Research focuses on the ageing processes of the skin and the immune system. Here, the disturbed cell-cell and cell-matrix interactions as well as disturbances in the function of stem cells and resident cells in the epidermis and dermis play a hitherto poorly understood role. Especially with the demographically increasing ageing of people and our patients, understanding the fundamental mechanisms of the ageing processes of various organs, particularly the skin including the immune system, is of outstanding importance. This is because disorders of signalling pathways in ageing processes lead to wound healing disorders, loss of regenerative capacity and immune senescence, resulting in an increase in allergic reactions and autoimmune diseases (including bullous dermatoses, psoriasis vulgaris, autoimmune diseases from the group of collagenoses), infections and malignant tumours. It has recently become increasingly clear that substances released from the connective tissue (senescence-associated secretory phenotype) and immune senescence - in addition to autologous mutations of tumour cells - promote the progression of malignant tumoursof the skin (malignant melanoma, spinocellular carcinoma, cutaneous lymphomas). Cellular, molecular biological and biochemical approaches are used for research. We have very well-equipped laboratories with close links to preclinical institutes and centralised facilities that are equipped with state-of-the-art technologies.

At the Department of Dermatology and Allergology in Ulm, we endeavour to bring new treatments to the clinic by researching fundamental mechanisms and, conversely, to break down clinical observations in the laboratory in order to develop new preventive and therapeutic approaches for our patients through an improved understanding of pathogenesis. In addition 2 clinical study centres are active to test new therapeutic strategies in multicentre studies and to improve the side effects of modern targeted therapies.

The clinic has a particular interest in clinical research and interdisciplinary networking with neighbouring disciplines. The latest targeted therapies for inflammatory and malignant skin diseases (psoriasis, atopic dermatitis, autoimmune diseases, autoinflammatory syndromes, malignant tumours and lymphomas) are carried out in the clinic, further developed and used for new indications.

The working groups and their focal points are explained in more detail below:

Prof Karin Scharffetter-Kochanek working group

Working group Professor Johannes Weiss, MD

Working group Priv.-Doz. Dr Sebastian Iben

Working group Priv.-Doz. Dr med. Anca Sindrilaru

Working group Priv.-Doz. Dr Christiane Pfeiffer

Working group Priv.-Doz. Dr Thorsten Peters

External professors associated with the Chair of Dermatology and Allergology

Prof. Dr Lars-Alexander Schneider (Ulm)

Prof. Dr Margit Huber (Landshut)

Fibroblast senescence (Dr Pallab Maity, Dr Karmveer Singh, Linda Krug, Heidi Hainzl, Dr Meinhard Wlaschek)

The skin is regarded as a "marker organ" for the ageing of internal organs. We are pursuing the hypothesis that the ageing of connective tissue and the fibroblasts located in it play a significant role in the ageing of organs and the entire organism.

Fibroblasts do not undergo apoptosis if they have molecular damage to their DNA, but activate cell cycle checkpoints such as p16, which lead to the activation of an irreversible senescence programme with complete growth arrest. This means that the senescent fibroblasts accumulate in the dermis and are activated by the release of pro-inflammatory cytokines, chemokines and matrix-degrading metalloproteases (Senescenceassociated secretory phenotype- SASP) leads to changes in the endogenous niche and to the ageing of other skin tissues, such as the epidermis, subcutaneous connective tissue and hair follicles. In recent years, we have been able to identify a transcription factor that mediates fibroblast senescence and is simultaneously responsible for the suppression of the growth factor insulin growth factor-1 (IGF-1).

Unresolved questions: We are currently investigating the consequences of long-term activation of the transcription factor for fibroblast-specific senescence in human skin. In addition, we would like to develop inhibitors of the transcription factor that act exclusively in senescent fibroblasts. The neutralisation of individual factors of the secretory phenotype of senescent fibroblasts could also be of interest for the preservation of the tissue. Senolytics, substances that specifically lead to the cell death of senescent cells, are also being pursued by us and numerous researchers as an anti-ageing concept. In murine models, scientists have already been able to demonstrate the rejuvenation of ageing organs by depleting senescent cells. This would be very interesting, as senescent fibroblasts are not only responsible for the ageing phenotype, but also for the spread of tumours, wound healing disorders and presumably ageing and diseases of other organs.

Immune senescence in skin ageing processes(Albert Koroma, Ph.D. student, Dr Pallab Maity)

During physiological processes in embryogenesis and acute wound healing, senescent cells and fibroblasts do occur, which are very effectively cleared by cells of the native immune system. This effective clearance of senescent cells does not take place in ageing tissues, or only to a limited extent. This results in the persistence of senescent cells that release soluble factors such as chemokines, cytokines, matrix-degrading metalloproteinases and others. These soluble factors are part of the senescence-associatedsecretoryphenotype(SASP). The SASP released by fibroblasts can also transmit senescence to neighbouring cells, leading to tissue disintegration of the skin and probably other organs.

We are interested in whether macrophages (MΦ) and natural killer cells (NK cells) are no longer able to clear senescent fibroblasts from the tissue during immune senescence, or whether senescent fibroblasts themselves inhibit the immune cells from clearing the tissue. To this end, techniques are currently being investigated in cell culture with analyses of perforin and granzyme as well as phagocytosis activity of the cells of the native immune system. Murine models with deficient NK cells and macrophage populations are also being characterised in order to gain a better understanding of the in vivo significance of these cells in the clearance of senescent cells.

Unresolved questions: Can the activation of cells of the native immune system lead to better clearance of senescent cells and thus to the prevention of tissue ageing? Is it conceivable to successfully carry out a cell-based therapy with young or pharmacologically treated autologous cells of the native immune system in order to remove senescent cells from the tissue?

The importance of senescent fibroblasts in the progression of malignant tumours of the skin (Dr Abhijit Basu, Dr Vida Farsam (Alumna), Susanne Schatz)

In addition to mutations of keratinocytes and melanocytes that lead to malignant tumours such as spinocelular carcinoma and malignant melanoma during oncogenesis, the importance of peritumoural connective tissue has increasingly become the focus of research.At the Department of Dermatology and Allergology at Ulm University Hospital, we are investigating how senescent fibroblasts influence tumour progression in spinocelular carcinomas and malignant melanoma. We are particularly interested in the release of factors of the Senescenceassociated secretory Pphenotype (SASP) of senescent fibroblasts. Using antibody arrays and RNA Seq technology, we were able to elucidate the SASP of senescent fibroblasts. We identified the chemerin released by senescent fibroblasts, a chemokine that binds to corresponding receptors of malignant spinocellular carcinoma cells via the MAP/Jun kinase signalling pathway and promotes their migration and invasion into the dermal connective tissue.

A set of chemokines was also identified that induces migration, invasion and growth of primary melanoma cells and melanoma cell lines in vitro and in vivo in preclinical models. The identified chemokines were also detected in tissue from spinocellular carcinomas and melanomas from older patients, but not from younger patients. These data show that the peritumoural connective tissue plays a central role in the progression of malignant skin tumours, a role that has been little researched to date.

Unresolved questions: The signalling pathways of these chemokines released by senescent fibroblasts are now being elucidated in order to therapeutically interrupt the signalling pathway in a targeted manner. This procedure will enable preventive and therapeutic approaches in the long term.

Mesenchymal stem cells in ageing processes (Philipp Haas, Ph.D. student, Dr Karmveer Singh, Dr Juliane de Vries (alumna), Dr Seppe Vander Beken (alumnus), Heidi Hainzl)
The ^ABCB5+ MSC have a preference in their endogenous niche. They either reside near vessels or in the interstitial dermis. We are currently investigating whether this subpopulation can be altered by the transcription programme after exposure to the bacterial wall component LPS (lipopolysaccharide), similar to adipose-derived MSCs. In addition, we are investigating whether this "priming" of LPS-pretreated ^ABCB5+ MSC prior to transplantation also leads to improved wound healing in preclinical models.

We have observed this for adipose tissue-derived MSCs (Munir, Basu et al., 2020). The dissertation by Mr Philipp Haas investigates whether ^ABCB5+ MSC are also capable of this adaptive response with rapid transcriptome conversion and whether ^ABCB5+ MSC from young and old donors react differently. This could be of clinical significance if older donors are less able to adapt the transcriptome qualitatively and quantitatively to LPS and thus presumably less able to respond to infections. Ultimately, results from this line of research into the adaptive responses of mesenchymal stem cells will also help to improve and clinically utilise MSC-based therapies for the treatment of infected wounds and chronic wounds.

Unresolved questions: How can the endogenous niche be manipulated to better characterise mesenchymal stem cell tissue regeneration and wound healing, and how can the endogenous niche be manipulated to influence tissue regeneration and wound healing? Search for ways to improve stem cell therapies.

(PD Dr Anca Sindrilaru,Dr Seppe Vander Beken (alumnus), Dr Juliane de Vries (alumna), Dr Abhijit Basu, Dr Karmveer Singh, Dr Pallab Maity, Dr Dongsheng Jiang (alumnus), cand. med. Oliver Storz, Heidi Hainzl, Linda Krug, Susanne Schatz)

For many years we have been interested in wound healing disorders, their causes and new therapeutic options. Chronic wounds increase significantly with age up to 4 to 5 % and already affect a large proportion of our population. We were able to show that chronic wounds are caused by a persistent inflammatory reaction (Wlaschek and Scharffetter-Kochanek, 2005, Wlaschek et al., 2019, Sindrilaru et al., 2011). The wound healing process cannot switch from this inflammatory phase to the next phase of wound healing. This failure to switch from the inflammatory phase to the phase of granulation tissue formation (replacement tissue) is the cause of various chronic wounds such as venous ulcers, diabetic foot ulcers (mal perforans) and decubital ulcers. Iron overload and the insulin resistance that develops under oxidative stress play a decisive role here. In recent years, we have been working on the question of whether mesenchymal stem cells can recognise the specific and different situations of different wounds via certain "sensing mechanisms" and can adapt their transcriptome very quickly to the respective situation. We have investigated this hypothesis in acute and a number of chronic wound models. The special feature of these wound models is that they can mimic the pathogenesis of a chronic venous ulcer, a diabetic ulcer, an infected environment and vasculitis. It is interesting to note that these different situations cause very specific transcriptome changes in the MSC, which then act on different cells via the release of soluble factors and can significantly accelerate the delayed process of wound healing (Qi et al. 2014, Jiang et al., 2013, 2016, Jiang and Scharffetter-Kochanek 2016, 2020). This sensing of the environment with a different MSC response in each case is presumably an evolutionarily optimised process that serves the MSCs to defuse the different hostile conditions in their neighbourhood in order to protect their DNA. This is because MSC self-renewal relies on intact DNA as a blueprint for daughter cells with self-renewal potential.

^ABCB5+MSCaccelerate the healing of chronic venous ulcers

When ^ABCB5+ MSC are transplanted into chronic iron-overloaded wounds, wound healing of these chronic wounds is accelerated (Vander Beken et al., 2019). ^ABCB5+ MSC preferentially release interleukin-1 receptor antagonist (IL-1RA), which prevents the binding of IL-1β and thus inhibits the activated inflammasome. This also leads to a switch from pro-inflammatory M1 macrophages to regenerative, anti-inflammatory M2 macrophages in the ulcer. This leads to the healing of the inflammation and, via the release of growth factors from the M2 macrophages, to the formation of granulation and replacement tissue. This means that ^ABCB5+ MSC are able to overcome the blockage of the chronic venous ulcer in the inflammatory phase and heal the wound.

^ABCB5+MSCsas "adaptive drug stores" - studies on clinical use

According to these studies, human dermal ^ABCB5+ MSCs also represent a promising therapeutic option for chronic venous ulcers in humans. The ^ABCB5+ MSCs were initially tested according to GLP guidelines and developed for GMP-compliant use as medical devices in accordance with the guidelines (Tappenbeck et al., 2019). Initial multi-centre studies on therapeutic use were initiated by TICEBA and RHEACELL (EudraCT Number: 2015-000399-81, 2017-000233-31, 000234-57) and have shown very good healing rates in chronic venous ulcers as well as diabetic ulcers. These need to be confirmed in larger studies.

In the long term, differently "primed" MSCs are to be developed for the healing of infected wounds.

(Dr Rajeev Pandey, Dr Kamayami Singh, Prof Honglin Wang )

We have generated the hypomorphic (CD18hypo) PL/J mouse model together with Prof Beaudet and his team (Baylor College of Medicine in Houston, Texas). These mice exhibit reduced expression of the common chain of β2 integrins (CD11/CD18) and spontaneously develop T-cell-mediated psoriasiform skin disease. This psoriasis mouse model strongly resembles human psoriasis clinically and histologically in its T-cell-dependent pathogenesis, polygenic basis and response to therapy. Depleting antibodies against CD4+, but not CD8+ T cells, led to complete resolution of this psoriasiform skin disease. CD18 represents the common β2 chain of the β2 integrin family, with 4 heterodimeric molecules (CD11a/CD18, CD11b/CD18, CD11c/CD18 and CD11d/CD18) expressed exclusively on haematopoietic cells. Among other possibilities, reduced CD18 expression can cause impaired formation of the immunological synapse, leading to the generation and persistence of autoreactive T cells. We were able to show that the reduced expression of CD18 leads to an increased formation of Th17 cells at the expense of regulatory T cells. This mouse model allows us to use genetic methods to elucidate the polygenic nature of this disease, in particular of genes that are partly responsible for the psoriasiform phenotype, in addition to the reduced CD18 expression.

Questions: Which genes are partly responsible for the psoriasiform genotype? The pathogenic role of _β2 integrins in human psoriasis and other inflammatory skin diseases is poorly understood.

Third-party funded projects

German Research Foundation (SFB1149 Trauma, GRK1789 CEMMA, grant for individual applications), BMBF, European Union, Excellence Initiative International Graduate School Ulm/IGradU, industrial co-operations, Landesstiftung Baden-Württemberg.

Medical doctoral theses

We award experimental doctoral theses that are orientated towards questions in the main research areas presented. A scholarship is applied for together with the candidate. Close supervision in the seminar and outside. Training in modern techniques on the research question and teaching of general concepts of medicine is sought. A full-time commitment is required for 12 months.

Scientific doctoral theses

We award experimental doctoral theses that are orientated towards questions in the main research areas presented. Candidates can either aim for a Dr. biol. hum. from the Faculty of Medicine or, depending on their qualifications, a PhD or Dr. rer. nat. from the International Graduate School Ulm.

Prof Weiss' research group has spent years investigating the role of dendritic cells in the context of allergic skin reactions and inflammatory skin diseases. In recent years, a particular focus has been on the role of osteopontin (OPN), a protein with diverse functions that exerts cytokine functions in the immune system and is secreted by various immune cells. Most recently, the role of osteopontin was investigated in particular in the context of chronic allergic contact dermatitis. It was shown that the retinoid 9-cis-retinoic acid (9cisRA), which is also used to treat hand eczema, induces the differentiation of a special regulatory dendritic cell phenotype. Dendritic cells treated with 9cisRA express lower levels of the MHC-2 complex and co-stimulatory molecules, but increased levels of the inhibitory co-receptor PDA-1 ligand. 9cisRA-treated dendritic cells express fewer pro-inflammatory cytokines, but express high levels of osteopontin and induce regulatory T cells (Treg). The osteopontin secreted by dendritic cells is obviously of particular importance for Treg differentiation, as OPN-deficient dendritic cells are less able to induce Tregs.

The aim of the project is to determine plasma cytokines, in particular OPN and Th17 cytokines, in the serum of psoriasis patients as part of routine clinical psoriasis therapy. The survey was carried out as part of the psoriasis consultation hours at the Department of Dermatology and Allergology.
Abstract from the project at FoBi-Digital 2020
The modulation of the IL-17/osteopontin axis in psoriasis during the course of the disease and in comorbidities under "real-life" conditions
Julian Schmid, Lea F. Kraus and Johannes M. Weiss
University Clinic for Dermatology and Allergology Ulm
Osteopontin (OPN) has pro- and anti-inflammatory cytokine effects. In multiple sclerosis, OPN from dendritic cells induces the production of IL-17 in CD4+ T cells and perpetuates inflammation. High OPN levels have been associated with comorbidities in psoriasis patients. The aim of the project was to investigate the influence of therapy on OPN plasma levels in psoriasis patients under the "real-life" conditions of a psoriasis consultation using existing routine samples, to place these in the overall context of cytokine regulation and to correlate the cytokine patterns with the course of the disease and comorbidities.
Data from 148 consecutive psoriasis patients presenting at the University Clinic for Dermatology Ulm were analysed at two treatment time points (T1 and T2) using a serum/plasma sample bank. The treatment modalities ranged from local therapy to biologics. Data from 118 patients (73 men and 45 women, average age 53 years) were analysed. IL-12, IL-17, IL-23, IFNγ, TNFα, IL-4, IL-10 and OPN were determined in serum/plasma.
Only low concentrations were found for IL-4, IL-10, IL-12 and IL-17, higher concentrations for IL-23, IFNγ and TNFα. At the same time, OPN was strongly elevated in plasma. Between time point T1 and T2, the mean cytokine concentration of IL-4, IL-10, IL-17, IL-23 and OPN tended to decrease, whereas IL-12, TNFα and IFNγ increased slightly. The OPN concentration correlated negatively with the Th2 cytokine IL-4 and positively with anti-inflammatory IL-10 (T2). The evaluation of patients with a good response to therapy (ΔPASI ≤ -5) showed a significant increase in IL-10 and IL-4 as well as a reduction in IFNγ, but not in OPN.
With regard to comorbidities, a significantly higher OPN concentration was found in patients with hypertension (T1) and with severe psoriasis > 10 years. Physically inactive patients, diabetics (T2) and patients with psoriatic arthritis (T1) had a higher IL-12 concentration, nicotine users had a higher IL-23 concentration.
In summary, this study indicates that pro-inflammatory cytokines are increased in certain comorbidities. It is confirmed that OPN is detectable in high concentrations in psoriasis. A significant modulation of OPN under therapy could not be demonstrated.

Project staff:
Julian Schmid
Lea Kraus, MD

The project was supported in part by Novartis Pharma GmbH.

Research project "Psoriatic arthritis and comorbidities in psoriasis: an interdisciplinary project for health services research"

This is a project in which a patient questionnaire is used to survey the care situation with regard to psoriatic arthritis and psoriasis comorbidities in the Ulm area. The data will be collected as part of an interdisciplinary psoriasis consultation. The project partner is the Rheumatology Department at the Alb-Donau Clinic in Langenau, Dr Steffen Briem.

Doctoral students in the project:
Ms S. Thiess
Ms C. Eckert
Ms S. Prox-Ambil

The project is partially supported by Novartis Pharma GmbH.

NSAID intolerance

Retrospective observation of patients with analgesic hypersensitivity

Summary of the dissertation Dr Martin Winter, MD

NSAIDs (non-steroidal anti-inflammatory drugs) are among the most frequently prescribed medications and are the second most common suspected trigger for drug hypersensitivity after antibiotics. Due to various pathomechanisms, the triggering agent is often neither clearly identifiable nor a guarantee that other NSAIDs can be taken safely. The gold standard for the diagnosis of drug intolerance is drug provocation testing.
The aim of the study was to analyse the correlation between proven analgesic intolerance, severity of the clinical reaction during provocation testing, increased mast cell tryptase in the serum, relevance of skin testing for the diagnosis of analgesic hypersensitivity, older age and tolerance of other COX inhibitors (cyclooxygenase inhibitors) (particularly COX-2 inhibitors). For this purpose, 438 patients from 2004 to 2014 who received drug provocation at the Department of Dermatology and Allergology at the University of Ulm were examined. The analysis showed that an older age (> 60 years) is not associated with an increased prevalence of analgesic intolerance. Clear risk factors indicating an increased prevalence could not be seen in either age or gender distribution.
Increased mast cell tryptase is an indicator of systemic mastocytosis and thus a higher risk of severe anaphylactic reactions. In the study population, the prevalence of elevated mast cell tryptase corresponded to the normal population, but only one patient in the group with proven drug intolerance had elevated mast cell tryptase. Compared to the other study patients, however, elevated mast cell tryptase is not a risk factor for a more frequent or more severe anaphylactic reaction in the drug provocation test.
COX-2 inhibitors are tolerated by 96% of all patients with proven NSAID hypersensitivity. There are isolated cases of both type I and type IV sensitisation to one COX-2 inhibitor (celecoxib), but only one patient reacted to another (predominant) COX-2 inhibitor (nimesulide). Nevertheless, the study shows that COX-2 inhibitors are very likely to be tolerated if there is intolerance to a COX-1 inhibitor. Nevertheless, the first dose should be taken under medical supervision and emergency preparedness.
In summary, this retrospective study shows that in 438 patients who received drug provocation at the Department of Dermatology and Allergology at Ulm University Hospital between 2004 and 2014, older age (> 60 years) is not associated with an increased prevalence of analgesic intolerance. Also, an elevated mast cell tryptase (≥ 11.4 μg) in patients receiving NSAID provocation testing is not a risk factor for a severe anaphylactic reaction. In addition, COX-2 inhibitors were tolerated by 96% of all patients with proven NSAID hypersensitivity. Accordingly, almost all COX-2 inhibitors were tolerated even in the presence of intolerance to a COX-1 inhibitor.

Link to the dissertation: https://oparu.uni-ulm.de/xmlui/handle/123456789/8146

Collaborators of the project:
Dr Christian Martin Winter

Expression of osteopontin in the context of the inflammatory reaction in psoriasis vulgaris, Susanne-Katharina Höppner, 2012 oparu.uni-ulm.de/xmlui/handle/123456789/2774
Insect venom allergy: Comparison of children and adults with regard to diagnostic parameters and tolerability of specific immunotherapy at the University Clinic for Dermatology and Allergology Ulm, Christina Schachtner, 2012 oparu.uni-ulm.de/xmlui/handle/123456789/2736

The expression of osteopontin and its receptors in allergic contact dermatitis, Tanja Uebele, 2013 oparu.uni-ulm.de/xmlui/handle/123456789/3062

The role of osteopontin in the chronification of allergic contact dermatitis, Anne Seier, 2008 (Dr biol. hum.)

The role of manganese superoxide dismutase for the function of dendritic cells, Christine Weber, 2015

Influence of different port catheter systems on the flow rates during extracorporeal photopheresis, Annerose Straub, (2016) oparu.uni-ulm.de/xmlui/handle/123456789/4027

Recombinant allergens in the diagnosis of hymenoptera venom allergy, Andreas Benedikt Weins, 2016

9-cis-retinoic acid modulates dendritic cell differentiation towards a regulatory T cell inducing phenotype, Lea-Franziska Kraus, 2018 oparu.uni-ulm.de/xmlui/handle/123456789/5503

Retrospective observation of patients with analgesic hypersensitivity, Christian Martin Winter, oparu.uni-ulm.de/xmlui/handle/123456789/8146

Medical dissertations are supervised. In order to guarantee good supervision, only a few theses are awarded at the same time. Currently, theses are mainly awarded in the field of healthcare research and clinical allergological research. A semester off is required to complete a dissertation, during which you can devote yourself fully to the project in the lecture-free period before and after the semester off.

(Fatima Khalid, Tamara Phan, MingYue Qiang, , Gaojie Zhu, Adrian Schelling, Maximilian Wagner, Sarah Müller) (Fatima Khalid, Tamara Phan, MingYue Qiang, , Gaojie Zhu, Adrian Schelling, Maximilian Wagner, Sarah Müller)

The skin and its appendages are our index organ for estimating a person's age. This is why we are investigating the mechanisms that cause the skin and the organism to age. Diseases in which genetic defects lead to accelerated ageing serve as a model for us to elucidate these mechanisms. Cockayne syndrome and trichothiodystrophy are related diseases in which genetic defects lead to accelerated ageing. Already in childhood, symptoms of ageing are seen in these patients, with loss of subcutaneous fat, hair loss, degeneration of the central nervous system and failure to grow and develop. We are studying skin cells from these patients to understand which cellular signalling pathways are disrupted. We are focussing our work on the investigation of ribosome biogenesis, as the genetic defects that cause the diseases also disrupt the production of the protein factories, the ribsomes. What are the cellular and organismal consequences of disrupted ribosome biogenesis? Can the lack of growth and the degeneration of the central nervous system in particular be explained by defects in the protein factories? The initial results of our work point in this direction. We were able to show that a "vicious circle" is active in the skin cells of Cockayne syndrome patients, which suppresses the growth of the cells. Work over the past decades has shown that all genes whose defects trigger Cockayne syndrome also play a role in ribosome production. If this synthesis is disrupted, ribosomes are also produced that are susceptible to errors. These ribosomes produce faulty proteins that stress the cells and lead to a response that suppresses the synthesis of new ribosomes. As a result, the cells have too few protein factories, and the protein factories that are produced work incorrectly. This vicious circle can be broken, at least in the cell culture dish, by the administration of protein chaperones. The suppression of ribsome biogenesis and protein synthesis is cancelled.

Cockayne syndrome - which changes in the ribosomes lead to a loss of protein balance?

(Dr Marius Alupei (alumnus), MingYue Qiang)

In skin cells of Cockayne syndrome patients, we were able to detect defective protein synthesis (Alupei et al, 2018). This leads to a loss of protein homeostasis and its cellular consequences. We are now investigating which changes in the ribosomes lead to the deteriorated quality of protein synthesis. The maturation of ribosomal RNA is being investigated, as well as the composition of ribosomes in mass spectrometric analyses and Western blots. Unresolved questions: Is the composition of ribosomes altered in Cockayne syndrome patient cells and could these changes explain the inaccuracy of protein synthesis? Is the synthesis of ribosomes normalised by the administration of pharmaceutical chaperones? Do the mouse models of Cockayne syndrome also show a loss of protein homeostasis and can this be treated by chaperone administration?

Trichothiodystrophy- characterised by a loss of protein homeostasis?

(Fatima Khalid, Tamara Phan)

Trichothiodystrophy is a disease related to Cockayne syndrome which, in addition to growth disorders and signs of premature ageing, is characterised by a typical skin and hair phenotype. The molecular cause of this disease is the subject of intense debate and these projects are investigating whether defective ribosomes are involved in the development of the disease. To this end, the researchers involved are each investigating two mutations in different genes, all of which lead to trichothiodystrophy. Unresolved questions: Do we find the same disease mechanisms in trichothiodystrophy as in Cockayne syndrome? Are these cells also characterised by a loss of protein homeostasis and can this be treated by administering pharmaceutical chaperones? Do these chaperones work in the mouse model of trichothiodystrophy?

Disorders of protein synthesis at the ribosome as the basis of neurodegenerative diseases

(Maximilian Wagner (Alumnus), Sarah Müller)

Cockayne syndrome and trichothiodystrophy are model diseases that are used to understand the basic mechanisms of ageing diseases. In this project, we are investigating whether the knowledge gained from the study of pre-ageing diseases can be applied to typical ageing diseases. Since neurological diseases are characterised by a loss of protein homeostasis and Cockayne syndrome and trichothiodystrophy patients show neurodegenerative symptoms, we are investigating whether ribosome involvement is also detectable in typical neurodegenerative diseases such as Huntington's disease or Parkinson's dementia. We want to check whether findings from skin research have general validity. Unresolved questions: Do we find disorders of ribosome biogenesis inneurodegenerative diseases such as Huntington's, Parkinson's, Alzheimer's and amyotrophic lateral sclerosis? Can these disorders explain the loss of protein balance and do these disorders lead to nerve cell death?

Third-party funded projects

Our work is funded by the German Research Foundation DFG (Research Training Group 1789 CEMMA, individual application) as well as the European Huntington's Disease Network EHDN).