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Epigenetics, gene expression through mRNA and rRNA, pharmacogenomics in Alzheimer's disease and aging


Alzheimer's disease (AD) is a neurodegenerative, progressive and irreversible disorder. Early onset AD is generally familiar and exhibits an autosomal dominant inheritance pattern, while late-onset AD occurs in sporadic cases, shows a complex inheritance pattern and a high heritability. Human aging process also is a complex phenomenon involving genes and environmental factors. This project proposal is: 1) to investigate epigenetic regulation in genes related to AD and aging through DNA methylation frequency; 2) to correlate the DNA methylation frequency with gene expression through mRNA; 3) to correlate the DNA methylation frequency with ribosomal RNA levels (rRNA); 4) a pharmacogenomic study, to determine the correlation between the pharmacological response in patients and the presence of some genes polymorphisms. The following genes were selected for the epigenetics study: LR11, SNAP25, SIRT1, CNP, HSC71, GRP75, DRP-2 and SUV39H1, involved in amyloidogenesis, synaptic transmission, neuronal death, development of central nervous system and potential regulation of rDNA. Methylation DNA pattern will be performed through DNA modifications by sodium bissulfite conversion and Methylation Specific PCR Real-Time. Samples from three nervous system regions from 30 AD patients, 30 age and sex-matched controls, 50 blood samples from AD patients, 50 from elderly individuals, 50 from young individuals and 50 from cord blood samples of normal neonates will be analyzed. Gene expression will be evaluated using quantitative RT-PCR and hybridization with rRNA 28S and 18S fractions through Northern blotting. The pharmacogenomic approach will correlate the pharmacological response observed in patients with polymorphisms of APOE gene, related to lipid metabolism and CHNAR7, ChAT, AChE genes involved in acetylcholine pathways, the neurotransmitter implicated in AD etiopathogenesis and in pharmacological treatment. Our findings may provide new and incremental biological information related to the epigenetic regulation occurring in cerebral and blood tissues from AD and elderly controls, to the pharmacological response of AD patients concerning polymorphisms, to assist diagnosis, prognosis and to set some general and individual therapeutic conducts. (AU)

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