17. März 2009 17:30 Uhr, ZMBH, INF 282, Raum 512
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Sajjad Muhammad
AG Schwaninger, Pharmakologisches Institut der Universität Heidelberg
The HMGB1 receptor RAGE mediates ischemic brain Damage
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In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE (sRAGE) reduced the infarct size. In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE-/- bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1-RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.
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Tillmann Weber, Vera Baier, Dusan Bartsch
Abteilung Molekularbiologie, Zentralinstitut für Seelische Gesundheit, Mannheim
Transgenic mouse model for the development of new pharmacological and behavioral interventions enhancing neurogenesis in aging brain
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Only recently it has become accepted that neurons continue to be generated in the adult mammalian brain during the whole lifespan. Considering the potential of neurogenesis to restore neuronal function in aging and injured brain, it is essential to understand the mechanisms controlling neurogenesis in general, and in the in the aging brain in particular. Since molecular and biochemical mechanisms underlying adult neurogenesis are conserved in mammals, mouse transgenic models provide unique opportunity for developing and testing new pharmacological and behavioral strategies enhancing adult neurogenesis in aging brain. In addition, they provide an opportunity to asses the role of neurogenesis in functional and cognitive decline associated with normal aging.
We have developed new transgenic mouse model which allows simply, cost-effectively and reproducibly evaluate different pharmacological and behavioral strategies aimed at cognitive enhancement in old age. In addition, this model allows selective manipulation of genes in neuronal stem cells. Using this approach, we can follow long-term changes in both neurogenesis and neuronal survival induced by pathological conditions or therapeutic interventions, and correlate them to the cognitive performance. Since we selectively manipulate neuronal stem cells, novel treatments can be developed targeting earliest phases of neuronal proliferation and differentiation.
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Marianne Weires
AG Hemminki, Abteilung Molekulargenetische Epidemiologie, DKFZ Heidelberg
Relevance of random marital factors in cancer occurrence in Sweden
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Spouses may have an increased sharing of environmental risk factors during adulthood. An accurate quantification of the role of marital aggregation in cancer occurrence might provide valuable insights into the contribution of the environment to cancer development.
The 2008 update of the Swedish Family Cancer Database includes over 2 million individuals with common biological descendants, which were classified into four different categories according to number of children and age difference between youngest and oldest child. We investigated the marital correlation in age of cancer diagnosis by including a shared random marital effect (frailty) in the survival model. The strength of association between spousal survival times was measured by Kendall’s tau.
Our results confirm that a shared lifestyle during adulthood may be reflected in an excess concordance of cancer among spouses. The observed increase in marital correlation with time of cohabitation adds consistency to the present data.
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Stephan Herzig
Nachwuchsgruppe "Molekulare Stoffwechselkontrolle", DKFZ Heidelberg
Transcriptional checkpoints in aging-associated metabolic disorders
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Energy homeostasis during aging can range from excessive energy storage (e.g. obesity) to wasting hypermetabolism (e.g. sarcopenia/cachexia). Despite opposing substrate availability, energy overload and wasting share major phenotypical features, such as hepatic steatosis, insulin resistance, and chronic inflammation. This seminar will discuss recent progress in the identification of common and distinct transcriptional mechanisms in opposing states of energy homeostasis as associated with the aging process per se and exemplified by type II diabetes and obesity or starvation and (cancer) cachexia, respectively.
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