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Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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Institute of Biochemistry I - Pathobiochemistry Johann Wolfgang Goethe-University Faculty of Medicine
Our mission It is the intention to elucidate biochemical signatures with relevance to inflammation and hypoxia, thus contributing to Biomedical Research in the area of pathophysiological signal transduction (pathobiochemistry). It is hoped that our work adds to a better understanding of pathogenesis and therapeutic interventions during inflammatory/hypoxic disorders. We aim at understanding:
- Inflammation associated with malfunctions in oxygen metabolism - Tumor biology linked to macrophage polarization and lipid metabolism - Hypoxia / HIF-1α (hypoxia inducible factor-1α) and its role in Biomedicine
Introduction Our research interests center on physiological/pathophysiological signal transduction pathways of stress components, which is relevant for the comprehension of human disease. Various types of cellular stress such as redox-changes, a lack of oxygen (hypoxia), inflammation and/or cell demise promotes cell damage, repair or adaptation towards growth as well as differentiation. Endogenous defence mechanisms balance cell or tissue injury to allow progression towards healing, anti-inflammatory outcomes and cell survival. Understanding cell destructive pathways appears to be of considerable importance in proposing therapeutic means for areas in biomedicine when oxygen supply to cells/tissues becomes limiting (hypoxia/ischemia), during cancer, when macrophage polarization affects tumor biology, and when modulation of innate immunity is required to balance pro- vs. anti-inflammatory signals. Headlines characterizing our research Stability vs. expression regulation of HIF-1α under normoxia and hypoxia -Role of HIF-1α in coordinating inflammation and tumor development -Hypoxia as regulator of cell demise pathways, i.e. apoptosis and chemo-resistance
-Phagocytosis of apoptotic material in affecting innate vs. adaptive immunity oxLDL in modulating the macrophage phenotype -The impact of PPARγ in macrophages and T cells -Lipid mediators (e.g. sphingosine-1-phosphate)
Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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Keywords Apoptosis, hypoxia, nitric oxide, inflammation, macrophage polarization, oxLDL, HIF-1α, PPARγ, S1P Funding of our research is provided by
-Deutsche Forschungsgemeinschaft -Deutsche Krebshilfe -Wilhelm-Sander-Foundation -European Commission -Industry
Synopsis of Research Themes:
1) Hypoxia and HIF-1α at the crossroad of NO and superoxide signaling 2) Macrophage polarization and lipid signaling
3) PPARγ in directing pathways of innate immunity and early Inflammation
Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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1) Hypoxia and HIF-1α at the crossroad of NO and superoxide signalling Sensing and responding to changes in oxygen partial pressure assures the cellular oxygen supply to be tightly controlled to balance the risks of oxidative damage vs. oxygen deficiency. Responses to reduced oxygen supply are primarily linked to changes in gene expression and the action of hypoxia inducible factors (HIF). Episodes of hypoxia/reoxygenation (ischemia/reperfusion) are biochemically/clinically important during organ transplantation, stroke, or acute heart failure. Moreover, during wound healing or tumor development cells experience a decrease in oxygenation, which provokes adaptive responses ranging from full recovery to death. Among recent advances, are the discoveries that HIF-1 not only is responsive to hypoxia but also to normoxic regulation by cytokines, superoxide or nitric oxide (NO). The importance of NO and O2- in affecting target proteins such as HIF-1α with different outcomes under hypoxia vs. normoxia can be relevant to many patho-physiologic circumstances attributed to excess radical production or alterations in antioxidant defence systems. The HIF system has revealed an unexpectedly direct connection between molecular oxygen, superoxide and NO in achieving or attenuating responses to hypoxia. Understanding the multiple signals that have the potential to deliver a flexible and controlled response to hypoxia will be critical to develop therapeutic manoeuvres. Moreover, the role of HIF-1α in coordinating macrophage function appears relevant to understand the initiation and resolution of inflammation. Currently, we address the following thematic priorities:
-The role of NO and O2- in stability regulation of HIF-1α under normoxia vs. hypoxia -Calpain mediated destruction of HIF-1α in pVHL-negative cells under hypoxia/NO -Gene regulatory mechanisms elicited by hypoxia/NO -The contribution of hypoxia and/or HIF-1α in affecting chemoresistance of tumor cells -The impact of hypoxia/HIF-1α in macrophage polarization and 'education' of TAMs (tumor associated macrophages) -Metabolic activity of cells as a rheostat in expression regulation of HIF-1α
Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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Lipid mediators in tumor immunology
Immune cells are present in virtually all kinds of tumors in humans. Their potential
impact (the impact of inflammation) on oncogenesis has already been proposed in
the 19th century by Rudolf Virchow and has been a matter of extensive research in
the last decades. Immunity has the potential to induce tumor rejection but is also
linked in shaping the clinically detectable tumor phenotype through constant
interaction between immune cells and tumor cells. This dichotomy of being
programmed from a potentially tumoricidal to a tumor-promoting cell is probably true
for all tumor-infiltrating immune cell populations.
However, among immune cells infiltrating established tumors in humans and mice,
mononuclear phagocytes and especially macrophages stick out both in their tumor-
promoting ability as well as their number. The presence of tumor-associated
macrophages (TAM) is correlated to a poor survival prognosis in many solid human
tumors, especially in breast, prostate, ovarian and cervical cancer. TAM are involved
in virtually all stages of oncogenesis by acquiring different functional phenotypes
(indicating their ‘pleiotropic’ nature) in response to their interaction with neoplastic
cells and the local microenvironment. They have the potential to support tumor
survival/growth, metastasis, tumor angiogenesis and immune evasion.
The microenvironmental signals that direct tumor-supportive immune cell activation
are largely unidentified. Tumor development, i.e. the shaping and outgrowth of
malignant cells, as it is true for all evolutionary processes, is accompanied by death
of a large proportion of the whole cell population, which is why dying tumor cells can
be considered as a major tumor-enriched environmental niche. The interaction of
immune cells such as macrophages or dendritic cells with dying/apoptotic tumor cells
may be a major mechanism to activate them towards tumor promotion. Within this
process, we identified lipid mediators such as sphingosine-1-phosphate (S1P) or
prostaglandin E2 (PGE2), which are increasingly recognized in tumor biology, as key
molecules mediating TAM activation and function. We are interested to understand
the full impact of these and other bioactive lipids in immune cell activation by/in
tumors in vitro and in vivo. Along this line, we also study mechanisms and
consequences in tumor-derived lipid antigen presentation by TAM to natural killer T
cells.
Thematic Priorities
- Phenotype characterization of tumor-associated mononuclear phagocytes in murine
tumor models
- Formation and action of lipid mediators, e.g. S1P, PGE2 in models of macrophage/
DC activation
- Education of human macrophages by tumor cells in different stages of viability
(living/apoptotic/necrotic)
- Consequences of lipid antigen presentation in cancer
Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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3) PPARγ in directing pathways of innate immunity and early Inflammation PPARγ in macrophages and T cells The balance of pro- vs. anti-inflammatory immune responses controls innate immunity. Elucidating molecular mechanisms that provoke and/or allow to interfere with a dysregulated immune response gains considerable interest. Sepsis as a classical example being associated with a dysregulated immune response is characterized by either a hyper-inflammatory response (SIRS; systemic inflammatory response syndrome) or a hypo-inflammatory response (CARS; compensatory anti-inflammatory response syndrome). Disease progression is highly variable and dependent on the prevalence of one of the two responses. An established factor provoking an anti-inflammatory response is the nuclear hormone receptor PPARγ. On one side, PPARγ inhibits pro-inflammatory gene expression, predominantly by scavenging transcription factors and/or cofactors from binding to their cognate binding sites in promoters of target genes, while cytosolic localized PPARγ interferes with activation and translocation PKCα to attenuate downstream signaling cascades. On the other side, PPARγ provokes apoptosis, which might limit immune cell numbers explaining e.g. T cell depletion in sepsis. Therefore, understanding the role of PPARγ in modulating innate immune responses will be essential for proposing therapeutic interventions. Currently, we address the following thematic priorities:
-Cytosolic properties of PPARγ in attenuating PKC-signaling -Induction of apoptosis by PPARγ agonists -Expression regulation and activation of PPARγ during sepsis -Conditional PPARγ knockout mice
Research Themes / Institute of Biochemistry I – Pat hobiochemistry / Johann Wolfgang Goethe-University Faculty of Medicine
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