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Understanding how LAMA2 deficiency impacts organ homeostasis
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Resumo(s)
LAMA2-congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease which
manifests itself from birth and is caused by mutations in the LAMA2 gene. Although most studies have
focused on the role of LAMA2 in skeletal muscle, LAMA2 is also expressed in other organs. Preliminary
data from the host laboratory suggests that the absence of LAMA2 may lead to increased oxidative stress
and alterations in cell metabolism in organs such as the kidney and liver. Therefore, this project aimed
at addressing how the kidney and liver are affected during the onset of LAMA2-CMD, specifically
between embryonic days 17.5 and 18.5 (E17.5 and E18.5), using the dyW mouse model for LAMA2-
CMD. To explore how Lama2 deficiency affects organ homeostasis, pathways linked to oxidative stress,
mitochondria stability and glucose metabolism were analysed in order to compare between livers or
kidneys of WT and dyW mice at E17.5 and E18.5. Alterations in oxidative stress response were detected
in the liver and kidney at E17.5 and E18.5, with impaired mitochondrial function in dyW
kidneys.
Considering that the alterations were more predominant in the kidney, primary proximal tubule cells
were isolated from WT and dyW
foetuses, to further dissect the impact of Lama2 deficiency in this organ.
In vitro results showed no differences between WT and dyW
kidney cells. While this work highlighted
significant alterations in oxidative stress in vivo, particularly in the kidney, likely given its higher Lama2
expression, the Lama2 deficiency alone may not fully account for the alterations seen in the whole
organs of these animals, and these effects may diminish outside the in vivo context. Overall, this project
sheds new light into the mechanisms that link LAMA2 to cell homeostasis which may vary depending
on the type of organ and their intrinsic expression of LAMA2.
Descrição
Tese de mestrado, Biologia Evolutiva e do Desenvolvimento, 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Distrofia muscular com deficiência em LAMA2 Matriz extracelular Stress oxidativo Metabolismo Homeostasia Mitocondrial Teses de mestrado - 2024