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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES031086&format=word)
| Principal Investigator: Lloyd, R. Stephen | |
|---|---|
| Institute Receiving Award | Oregon Health & Science University |
| Location | Portland, OR |
| Grant Number | R01ES031086 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 Jan 2020 to 31 Oct 2024 |
| DESCRIPTION (provided by applicant): | Summary The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV) infection is associated with a significant increased risk for early onset hepatocellular carcinomas (HCCs) in millions of people living in East Asia, Central and South America, and sub-Saharan Africa. Even though dietary exposures to aflatoxins constitute the second largest global environmental risk factor for cancer development, there are still significant questions concerning the molecular mechanisms driving carcinogenesis. In-depth knowledge of these mechanisms is critical for the identification of genetic risk factors that affect individual susceptibility for people who are HBV infected and AFB1 exposed. In this regard, since AFB1 carcinogenesis is driven by high frequency G to T transversions, the DNA repair pathways that initiate and complete repair of persistent AFB1-induced DNA adducts and base damage from HBV-induced inflammation have strong biological significance. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Although the nucleotide excision repair (NER) pathway has been shown to repair AFB1 DNA adducts, murine data presented herein demonstrate that knockout of the DNA base excision repair (BER) pathway, initiated by the DNA glycosylase NEIL1, is significantly more important than NER relative to the removal of the highly mutagenic AFB1-Fapy-dG adducts. Thus, our data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To maximize relevance to human health, all known variants of NEIL1 will be characterized from regions of the world where aflatoxin ingestion and HBV infection are prevalent. All variants will be characterized for their biochemical properties relative to WT NEIL1 and expressed in cells and transgenic mice to understand the potential for catalytically- compromised variants of NEIL1 to alter susceptibility to aflatoxin exposures. These aims will test the hypothesis that expression of the oncogenic and other catalytically-compromised variants of NEIL1 can efficiently block repair and promote increased mutagenesis and carcinogenesis. Characterization of phenotypically dominant oncogenic variants of NEIL1 will provide the molecular basis from which to design human epidemiological studies in at-risk populations and early onset HCC cohorts. Further, this application proposes to establish the molecular mechanisms by which the combination of chronic inflammation driven by the hepatitis B surface antigen and deficiencies in DNA repair could synergistically drive AFB1-induced mutagenesis and carcinogenesis. Overall, these studies have direct human health relevance pertaining to understanding a global environmental health problem by identifying genetic risk factors and biochemical pathways previously not recognized as germane to AFB1-induced carcinogenesis. |
| Science Code(s)/Area of Science(s) |
Primary: 09 - Genome Integrity Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Michelle Heacock |