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![Role of Apurinic/Apyrimidinic Endonuclease 1 in Protecting Mouse Liver from Alkylation Damage için kapak resmi Role of Apurinic/Apyrimidinic Endonuclease 1 in Protecting Mouse Liver from Alkylation Damage için kapak resmi](/client/assets/d79c3e4af2b6d196/ctx/images/no_image.png)
Role of Apurinic/Apyrimidinic Endonuclease 1 in Protecting Mouse Liver from Alkylation Damage
Başlık:
Role of Apurinic/Apyrimidinic Endonuclease 1 in Protecting Mouse Liver from Alkylation Damage
Yazar:
Rodríguez Muñoz, Adlín Raquel, author.
ISBN:
9780438037892
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (116 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Carlos A. Torres-Ramos; Sylvette Ayala-Peña Committee members: María J. Crespo-Bellido; Sabzali Javadov; Jorge D. Miranda-González.
Özet:
Liver cancer is the sixth most common cancer worldwide and based on prevalence is second in mortality worldwide. A commonly used carcinogen for the study of cancer in rodents is azoxymethane (AOM) and the liver plays an important role in its bioactivation. AOM alkylates DNA bases inducing the formation of DNA adducts that, if left unrepaired, can lead to mutations and then carcinogenesis. DNA damage caused by alkylating agents is mainly repaired by the base excision repair pathway (BER), which includes the apurinic/apyrimidinic endonuclease 1 or APE1. In mice, the Apex1 gene encodes APE1. Homozygous deletion of the Apex1 gene is embryonic lethal but heterozygous animals (Apex1 +/-) have a normal lifespan. The role of APE1 in the repairing of damage induced by AOM in the liver is unknown. Our purpose is to study the role of APE1 in the repair of DNA lesions induced by AOM in liver. We hypothesize that APE1 deficiency will lead to increased DNA damage (both nuclear and mitochondrial), oxidative stress and tissue damage in liver from animals treated with AOM. To address this hypothesis, we adapted the PCR-based DNA damage detection assay (QPCR) for high throughput sample analyses. We incorporated a reference DNA to normalize data obtained from different QPCR experiments. Because of this change, the variation in PCR efficiency or product quantification between PCR plates was normalized. By doing this, we were able to analyze samples from different studies involving rat cardiomyocytes, peripheral blood mononuclear cells from patients with metabolic syndrome, breast cancer patients and the general population. Then, we studied the effect of Apex1 haploinsufficiency after a single injection of AOM in nuclear DNA (nDNA), mitochondrial DNA (mtDNA) damage and changes in mtDNA abundance in the liver. Our results show that acute treatment with AOM leads to increased mtDNA and nDNA damage in the liver, in both WT and Apex1+/- mice. Partial DNA repair was observed in mtDNA and the nDNA from both WT and Apex1 +/- mice, however, Apex1+/- mice display delayed mtDNA repair kinetics. In addition, in Apex1 +/- mice, mtDNA abundance is significantly increased 24 h after the AOM treatment followed by a decrease in abundance, 72 h after treatment. Expression analyses of genes involved in the antioxidant response show a trend characterized by decrease expression, 24 h after treatment, followed by a normalization of expression 72 h after expression. To study the role of APE1 in protecting the liver after chronic AOM treatment, we performed histology analyses of liver tissue. Histopathological lesions were observed in both WT and Apex1+/- mice, with higher levels of portal inflammation only in WT mice. Taken together our studies demonstrate that: (1) acute AOM treatment leads to both nDNA and mtDNA and that APE1 is involved in the repair of such lesions and in the maintenance of mtDNA abundance; (2) acute AOM treatment impacts the expression of genes involved in the antioxidant response, and; (3) Chronic AOM treatment induces histopathological changes and that APE1 may be involved in the response that leads to inflammation. Thus, we conclude that APE1 has multiple roles in the response toward alkylation damage in liver tissue.
Notlar:
School code: 0282
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(682588.1) | 682588-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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