Downstream effects of master regulators in two brain diseases.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

Abstract

In paper one, we investigated how the pharmacological activation and inhibition of the glucocorticoid system
affects lifespan and symptoms in a mouse model for RTT. We performed a long-term drug treatment study with
the GR activator corticosterone and the GR inhibitor RU486 under which we measured the lifespan and onset
of RTT-like symptoms of male Mecp2-null and female Mecp2 heterozygous mice in comparison to untreated
mutant and to treated and untreated wild-type animals. We could demonstrate that activation of the
glucocorticoid hormone system reduces the lifespan of Mecp2-/y mice and the symptom-free lifetime of
Mecp2+/- mice and that treatment with the GR inhibitor RU486 has an opposite effect as it prolongs the
lifetime until symptom onset for Mecp2+/- mice and improves motor functions of Mecp2-null male mice. Our
findings provide evidence for the contribution of the glucocorticoid hormone system to RTT motor symptoms
and suggests this system as a potential therapeutic target for RTT. In paper two and three, we focused on the
molecular events that lead to the development of primary malignant brain tumors. In paper two, we performed
a series of transplantation experiments with genetically perturbed cells. We could show that the individual
over-expression of potent oncogenes in neural stem/progenitor cells of the same cell pool leads to distinct
tumor types. Furthermore, we demonstrated that it is possible to convert one tumor type into another one and
that this is determined by the order of genetic events. In a second part of this study we could show a hitherto
unknown aspect of AT/RT and rhabdoid tumor biology, an activation of the UPR. We provide experimental
evidence that AT/RT and rhabdoid tumor cells with reduced or absent SMARCB1 levels are sensitive toward a
further increase in ER stress. In paper three, we studied the PcG protein BMI1 and its effect on neural
stem/progenitor cells and tumor formation. We observed a strong promotion of self-renewal, expansion and
survival in adult neural stem/progenitor cells upon over-expression of Bmi1 in vitro but found it incapable of
transforming cells as no tumors developed in intracranial transplantation experiments with Bmi1
over-expressing wild-type cells or Trp53-/- cells. Thus, we assume BMI1 to promote stem cell properties and to
act as a facilitator of transforming events induced by other oncogenes. Furthermore, we could identify four
novel direct BMI1 target genes whose molecular function may contribute to the known BMI1 effects, thus
expanding the BMI1 network. Taken together, the findings presented in this thesis emphasize the key role of
master regulators in the pathology of brain diseases and for the development of causal therapies.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Klinisk medicin
  • Cell- och molekylärbiologi

Nyckelord

Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
Handledare/Biträdande handledare
Tilldelningsdatum2012 sep 21
Tryckta ISBN978-91-87189-27-2
StatusPublished - 2012
PublikationskategoriForskning

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Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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