@phdthesis{Spitzel2023,
  author    = {Spitzel, Marlene},
  title     = {The impact of inflammation, hypoxia, and vasculopathy on pain development in the α-galactosidase A mouse model of Morbus Fabry},
  doi       = {10.25972/OPUS-34579},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345794},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by variants in the gene α-galactosidase A (GLA). As a consequence, the encoded homonymous enzyme GLA is not produced in sufficient amount or does not function properly. Subsequently, globotriaosylceradmide (Gb3), the target substrate of GLA, starts accumulating in several cell types, especially neurons and endothelial cells. FD patients suffer from multiorgan symptoms including cardiomyopathy, nephropathy, stroke, and acral burning pain. It is suggested that the impact of pathological Gb3 accumulation, inflammatory and hypoxic processes, and vasculopathy are contributing to the specific FD pain phenotype. Thus, we investigated the role of inflammation, hypoxia, and vasculopathy on molecular level in dorsal root ganglia (DRG) of the GLA knockout (KO) mouse model. Further, we investigated pain-like characteristics of GLA KO mice at baseline (BS), after capsaicin administration, and after repeated enzyme replacement therapy (ERT) administration for a period of 1.5 years. Acquired data showed disturbances in immune response markers represented by downregulated inflammation-associated genes and lower numbers of CD206+ macrophages in DRG of GLA KO mice. Hypoxic mechanisms were active in DRG of GLA KO mice reflected by increased gene expression of hypoxia- and DNA damage-associated targets, higher numbers of hypoxia-inducible factor 1α-positive (HIF1α+) and carbonic anhydrase 9-positive (CA9+) neurons in DRG of GLA KO mice, and DRG neuronal HIF1α cytosolic-nuclear translocation in GLA KO mice. Vascularization in DRG of GLA KO mice was reduced including lower numbers of blood vessel branches and reduced total blood vessel length. Pain-like behavior of the GLA KO mouse model revealed no mechanical hypersensitivity at BS but age-dependent heat hyposensitivity, which developed also age-matched wild type (WT) mice. Capsaicin administration under isoflurane anesthesia did not elicit the development of nocifensive behavior in GLA KO mice after mechanical or heat stimulation. Repeated ERT administration did not show a clear effect in GLA KO mice in terms of restored heat hyposensitivity to BS paw withdrawal latencies. In summary, we demonstrated the impact of disturbed immune response markers, active hypoxic mechanisms, and reduced vascularization on molecular FD pathophysiology.},
  subject      = {Fabry-Krankheit},
  language  = {en}
}
@article{PetritschKoestlerWengetal.2016,
  author    = {Petritsch, B. and K{\"o}stler, H. and Weng, A. M. and Horn, M. and Gassenmaier, T. and Kunz, A. S. and Weidemann, F. and Wanner, C. and Bley, T. A. and Beer, M.},
  title     = {Myocardial lipid content in Fabry disease: a combined \(^1\)H-MR spectroscopy and MR imaging study at 3 Tesla},
  series = {BMC Cardiovascular Disorders},
  volume    = {16},
  journal   = {BMC Cardiovascular Disorders},
  number    = {205},
  doi       = {10.1186/s12872-016-0382-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146693},
  year      = {2016},
  abstract  = {Background Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by \(^1\)H magnetic resonance spectroscopy (MRS) at 3 Tesla. Methods Myocardial lipid content was quantified in vivo by \(^1\)H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined \(^1\)H-MRS with cardiac cine imaging and LGE MRI in a single examination. Results Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076). Conclusions This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by \(^1\)H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; \(^1\)H-MRS; T\(_1\) mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.},
  language  = {en}
}