| 1. |
- Friberg, Hans
(författare)
-
Ischemic and Hypoglycemic Brain Damage, Involvement of the Mitochondrial Permeability Transition Pore
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Brain damage from ischemia-reperfusion and hypoglycemia are major causes of morbidity and mortality. Therapeutic strategies include hypothermia, glutamate-receptor blockade, immunosuppression and lately treatment aiming at preserving mitochondrial integrity and function. Mitochondria are the main producers of cellular energy but mitochondria also participate in cell signaling and take an active part in the life/death decision of a cell. Oxidative stress and high mitochondrial calcium loads can trigger the formation of a large pore in the mitochondrial inner membrane, the mitochondrial permeability transition pore. The consequent disruption of the mitochondrial membrane potential, osmotic swelling and loss of metabolites and mitochondrial proteins through a ruptured outer membrane may lead to immediate or delayed cell death. In this study we demonstrate that isolated mitochondria from different brain regions have different sensitivity to calcium-induced permeability transition and furthermore that this correlates with the selective vulnerability of these regions to ischemia-reperfusion injury. Also, important modulators of the pore such as Bcl-2 and free radical production are altered after ischemia. Thus, Bcl-2 levels decrease at 4h and at 24h after forebrain ischemia in parallel with a 50% increase of free radical production in mitochondria isolated from the vulnerable hippocampus. These alterations are not seen in isolated mitochondria from the more resistant cortex region. We also show that cyclosporin A and MeValCsA, potent blockers of the mitochondrial permeability transition pore, protect neurons from oxygen/glucose deprivation in vitro and from ischemia-reperfusion injury in vivo. Moreover, cyclosporin A protects mitochondria and neurons from hypoglycemic brain damage. We conclude that calcium-induced mitochondrial permeability transition differs between brain regions and that mitochondria from different regions respond differentially to ischemic stress. The results of the present thesis support the view that the mitochondrial permeability transition pore is of importance in the development of brain injury after ischemia-reperfusion and hypoglycemia.
|
|
| 2. |
- Frykholm, Carina, 1958-
(författare)
-
Clinical and Genetic Studies of Hearing Impairment
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Monogenic disorders offer a possibility for studies of genetic disturbances in hearing impairment—a knowledge which could be essential for development of future treatment options. In this thesis, the underlying genetic disturbances in neurofibromatosis 2 (NF2) and familial Meniere’s disease (FMD) were evaluated, and familial X-linked hearing impairment was described from a clinical point of view. In paper I, constitutional DNA from 116 individuals with NF2 of variable severity was studied using the array-CGH method focusing on a 7.6-Mb area surrounding the NF2 gene on chromosome 22q. Deletions were found in 20.7% of samples. In mild NF2, the deletions were small, but variable sizes of deletions were found in cases that were moderately or severely affected. Disease phenotype could not be predicted from the size of the deletions. In papers II and III, a single five-generation family with autosomal dominant FMD was described. Anticipation concerning age of onset was observed. Genome scan revealed five candidate gene regions with a LOD score of > 1. Two additional families with autosomal dominant MD were analyzed for linkage to these five regions. A cumulative Zmax of 3.46 was obtained for a single 463-kb region on chromosome 12p12.3, containing only one known gene: PIK3C2G. This encodes a protein with a proposed role in hair cell regeneration in mammalian ears. No mutations were found in protein-coding sequences or exon-intron borders. In two of the three families, a shared haplotype, suggested common ancestry, was found to extend over 1.7 Mb, which could be a genomic region of importance for FMD. In paper IV, a family in which five males displayed progressive low- and mid-frequency hearing impairment from the first or second decade was described. Female carriers were affected by a high-frequency hearing impairment from the fourth decade. The family could represent a novel X-linked dominant audiophenotype.
|
|
