Epigenetics is a priority area in the NIH Roadmap. The Epigenetic/Translational Biomarkers (ETB) core has the overall goal of consolidating and applying standard methods to detect epigenetic modifications, for use in preclinical models and translational studies on Projects 1-3 of the P01. This core integrates with all three projects on the P01, with specific emphasis on methodologies and services that will be used most heavily and routinely throughout the 5-year course of investigation. This core evolved out of the prior """"""""Services Core"""""""" and retains several key elements, such as the histopathology and biostatistics components. However, it now incorporates several epigenetic assays of importance to the central hypothesis of the P01: The CENTRAL HYPOTHESIS is that sulforaphane (SFN), indole-3-carbinol (I3C), and cruciferous vegetables from which they derive are effective chemopreventive agents because, in addition to their blocking activities, they alter the pattern of histone modifications and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the ceil cycle and apoptosis. Based on the central hypothesis, the following broad specific aims will be implemented in the ETB core:
Aim 1. Provide histopathology expertise for preclinical studies in rats and mice (Projects 1-3), and immunohistochemical analyses of epigenetic biomarkers (acetylated histones, HDACs) in animal and human tissues. The latter analyses will include tissue microarrays from translational studies with prostate cancer patients and colonoscopy patients.
Aim 2. Conduct routine HDAC activity assays on tissues from preclinical and clinical studies (Projects 1-3).
Aim 3. Run DNA methylation assays for epigenetically silenced genes of mutual interest (Projects 1-3). Arm 4. Perform LC/MS/MS analyses of SFN and I3C metabolites in tissues and body fluids (Projects 1-3).
Aim 5. Coordinate protocol design and statistical analyses of data (Projects 1-3). The long-term goal is to better understand which assays and biomarker(s) for epigenetic alterations in cancers might be applied in a reliable and robust manner in the clinical setting.
In addition to genetic changes affecting DNA sequence information, we now realize that cancer development involves so-called epigenetic events, which represent a major new research priority area at NIH. One aspect of intense current interest concerns the histone (protein) modifications that silence tumor suppressor genes in cancer cells. We find that dietary agents can reverse such modifications, thereby re-expressing tumor suppressor genes and triggering cancer cells to arrest their growth and/or commit suicide via apoptosis.
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