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Principal Investigator: Ohm, Joyce Ellen
Institute Receiving Award Roswell Park Cancer Institute Corp
Location Buffalo, NY
Grant Number R01ES034250
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 20 Mar 2022 to 31 Dec 2026
DESCRIPTION (provided by applicant): ABSTRACT Epidemiological evidence suggests that environmental exposures during development may play a role in disease susceptibility later in life, and researchers have hypothesized that epigenetic changes induced by common toxicants such as pesticides, herbicides, endocrine disruptors, and heavy metals may be facilitating this link1,2. The mechanisms by which these changes are induced and propagated remain challenging to dissect, largely because environmental toxicant induced changes are often 1) subtle when assayed across the bulk cell population, 2) transient in nature and therefore difficult to reproducibly detect, and/or 3) randomly distributed throughout the genome, making reproducibility and measurement of statistical significance challenging. In fact, most studies trying to link toxicant exposures directly to frank cellular transformation, including our own, have been relative failures. In virtually all cases, in order to see overt transformation, exposure studies need to be conducted in cell or animal models that already have baseline genetic or epigenetic changes that facilitate the progression to malignancy. We have exciting preliminary data that demonstrates that Ewing sarcoma cells demonstrate a significantly elevated level of transcriptional and replication stress (RS), and we propose that environmental exposures may not only induce RS and activate the RSR, but also cause epigenetic changes that precondition cells to allow for survival following expression of driver fusion proteins despite elevated levels of RS. This proposal will focus our efforts on understanding the downstream effects of TCDD exposures in mesenchymal stem cells (MSC) when paired with 2,4-D and 2,4,5-T and investigate the role of STAG2 in modulating downstream molecular events associated with environmental toxicant exposures. Our overall hypothesis is that environmental toxicant exposures cooperate with STAG2 loss to increase replication stress, ultimately leading to genomic and epigenomic instability, and creating a permissive epigenome for fusion gene expression. Three Specific Aims are proposed: SPECIFIC AIM 1: To determine whether environmental toxicant exposures increase baseline levels of replication stress in iMSC and cooperate with STAG2 loss to lead to epigenomic remodeling. SPECIFIC AIM 2: To determine whether environmental toxicant exposures cooperate with STAG2 loss to lead increased clonal genetic and epigenetic heterogeneity. SPECIFIC AIM 3: To determine whether environmental toxicant exposure leads to a permissive epigenome for survival of pre-malignant cells following fusion protein expression.
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Frederick Tyson