Ernst Schering Research Foundation workshop最新文献

Niche has become the most important issue in stem cell biology, but it is still a hypothetical notion that cannot be defined in a better way than the microenvironment surrounding stem cells. Using a melanocyte stem cell system as a model, we have analyzed the cellular and molecular requirements for differentiation of quiescent stem cells. Our results demonstrate the multiple subsets within the stem cell compartment and thus suggests the complexity of niche.

The cytokines IL-1alpha and IL-1beta have long been known to play a profound role in inflammation, and in the past decade another cytokine, IL-18 (originally known as IGIF), has also been realized to be an IL-1 family member and to possess significant inflammatory activity. Half a dozen additional members of the IL-1 family have been identified in recent years, and given their relatedness to IL-I and IL-18, it is tempting to speculate that they too might possess inflammatory potential. We have demonstrated that certain of these cytokines can activate MAP kinases and the pathway leading to NFkappaB, via known IL-1R family members. Moreover, when overexpressed in skin, they are capable of causing an inflammatory skin condition resembling that seen in human disease.

We pioneered anticytokine therapy (ACT) for autoimmune diseases (ADs). In 1974, we proposed that hyperproduced interferon (IFN) can bring AD and anti-IFN can be therapeutic. In 1989, we proposed removing tumor necrosis factor (TNF)-alpha together with certain types of IFN to treat various ADs. We found IFN in patients with different ADs and conducted the first clinical trial of ACT in 1975. Anti-IFN-gamma and anti-TNF-alpha work in similar ways, but the latter brings serious complications in some patients. We obtained good, sometimes striking, therapeutic effects treating many different Th-1-mediated ADs with anti-IFN-gamma, including rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, acne vulgaris, and others. Anti-IFN-gamma was in some ways superior to anti-TNF-alpha, which was ineffective in MS. Anti-IFN-gamma therapy holds great promise for treating many Th-1 ADs, especially skin diseases.

Dilated cardiomyopathy (DCM) is a fatal myocardial disease with an incidence of 40:100,000. In recent years, viral infection as a causative agent for myocarditis followed by DCM has become a main topic of research. On the one hand, the virus violates the myocardial integrity itself; on the other hand, the virus induces inadequate local humoral and cellular defense reaction resulting in cardiomyocyte death, fibrosis, and overall cardiac dysfunction. Classical virological approaches are no longer sufficient to detect and identify the virus in the heart. The possibility of endomyocardial biopsies, as well as the further development of new high-specific and sensitive molecular approaches including real-time PCR or sequencing, allows us to detect and to identify the patient- specific causal virus and to predict the progression of disease and hopefully, in the future, to develop virus-specific treatment strategies.

The nuclear receptors are ideal targets to control the expression of specific genes with small molecules. Estrogen receptor can activate or repress transcription though a number of different pathways. As part of an effort to develop reagents that selectively target specific transcriptional regulatory pathways, analogs of 4-hydroxytamoxifen were synthesized with variations in the basic side chain. In vitro binding assays and cell-based luciferase reporter gene assays confirm that all the derivatives have high affinity for the receptor and high potency at repressing direct estrogen receptor-mediated transcription.

Several HDAC inhibitors that exhibit impressive anti-tumour activity are now in clinical trials. Proteins that function in the same pathways might also serve as valuable therapeutic targets. A subset of histone deacetylase activities are found to be physically associated with ATP-dependent remodelling enzymes and may assist their function. This raises the possibility that ATP-dependent remodelling enzymes should be considered as therapeutic targets. Here some of the links between ATP-dependent chromatin remodelling enzymes and cancer are reviewed.

Regulation of chromatin structure is important for the control of DNA-templated processes such as gene expression and silencing, and its dysregulation is implicated in diverse developmental and cell proliferative defects such as tumorigenesis. Covalent post-translational modifications of histones are one of the prominent means to regulate the chromatin structure. Here, we summarize findings from our lab and others regarding the interactions between different covalent modifications of histones in the budding yeast Saccharomyces cerevisiae. First, we describe the effect of histone H3 phosphorylation at residue serine 10 in transcriptional gene activation, and its histone H3 acetylation dependent and independent modes of action and downstream effects on TATA-binding protein (TBP) recruitment. Further, we review how ubiquitylation of histone H2B and its deubiquitylation by ubiquitin proteases Ubp8 and Ubp10 regulate histone H3 methylations, and consequently affect co-activator-dependent gene transcription and silent chromatin, respectively.

There are few systems which enable adult tissue stem cells to be studied. However, the gastrointestinal tract with its high degree of polarity, well-defined cell migratory pathways, and dynamic cell replacement is a model tissue providing unique opportunities for stem cell study. Lineage tracking indicates that all cell replacement originates at well-defined stem cell positions, with an associated slower cell cycle. Radiobiological studies suggest a hierarchical stem cell compartment (actual and potential stem cells). Actual stem cells have an intolerance of genotoxic damage and die via apoptosis. Stem cells also selectively sort the old and new DNA strands at division, retaining the replication error free strands in the stem cell daughter. High genotoxic sensitivity and selective sorting of old and new DNA strands, provides extremely effective protective mechanisms against both replication and random errors. This provides a new explanation for the low cancer risk in the small intestine.

Psoriasis is a chronic autoimmune disease in which T lymphocytes are thought to be central in the pathogenesis. Recently, a T cell subset population was identified, whose role is to suppress inflammatory responses triggered by T effector cells. T cells in this new population are referred to as T regulatory cells. We studied their number and activity in psoriatic lesions and found that they are both numerically and functionally deficient in their ability to suppress the abnormally persistent psoriatic immune response. This deficiency may shed more light on the complex pathophysiology of psoriasis.