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1.
Front Mol Neurosci ; 12: 231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611772

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in profilin 1 were identified as a cause of familial ALS (fALS) in 2012. We investigated the functional impact of mutant profilin 1 expression in spinal cords during mouse development. We developed a novel mouse model with the expression of profilin 1 C71G under the control of the Hb9 promoter, targeting expression to α-motor neurons in the spinal cord during development. Embryos of transgenic mice showed evidence of a significant reduction of brachial nerve diameter and a loss of Mendelian inheritance. Despite the lack of transgene expression, adult mice presented with significant motor deficits. Transgenic mice had a significant reduction in the number of motor neurons in the spinal cord. Further analysis of these motor neurons in aged transgenic mice revealed reduced levels of TDP-43 and ChAT expression. Although profilin 1 C71G was only expressed during development, adult mice presented with some ALS-associated pathology and motor symptoms. This study highlights the effect of profilin 1 during neurodevelopment and the impact that this may have in later ALS.

2.
Biomaterials ; 32(34): 8957-67, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21872324

RESUMO

Identifying the critical molecules associated with "biocompatibility" is a grand challenge. Poly(methacrylic acid -co- methyl methacrylate) (MAA) beads improve wound closure and wound vascularity in vivo, but the mechanism of this phenomenon is unknown. We used quantitative real-time PCR to identify the subtle changes in the expression of a small selection of molecules involved in wound healing and angiogenesis in a macrophage-like cell (dTHP-1) treated with the MAA beads (45 mol% methacrylic acid). MAA beads decreased the expression of osteopontin (OPN) compared to poly(methyl methacrylate) (PMMA) and untreated cells, and increased the expression of IL-1ß, IL-6 and TNF-α over the 24-96 h of the experiment. Interestingly, molecules associated with angiogenesis, such as bFGF, CXCL12, HIF-1α, PDGF-B, TGF-ß and VEGF, were not significantly affected by MAA beads over the course of the study. MAA beads also increased the gene expression of OPN in HUVEC compared to untreated cells, while PMMA beads did not. MAA beads modified the phenotype (gene expression) of dTHP-1 cells in a subtle yet distinct manner that was different than PMMA. It remains to connect the changes in OPN in dTHP-1 (and HUVEC) and other molecules to the enhanced vascularity seen in vivo with this polymer.


Assuntos
Cimentos Ósseos/farmacologia , Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metilmetacrilato/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Polimetil Metacrilato/farmacologia , Cimentos Ósseos/química , Linhagem Celular , Células Endoteliais da Veia Umbilical Humana , Humanos , Macrófagos/metabolismo , Metilmetacrilato/química , Osteopontina/genética , Polimetil Metacrilato/química , RNA Mensageiro/genética
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