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Principal Investigator: Al-Hendy, Ayman
Institute Receiving Award University Of Chicago
Location Chicago, IL
Grant Number R01ES028615
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 11 Nov 2020 to 31 Jul 2022
DESCRIPTION (provided by applicant): Abstract Uterine Fibroids (UFs) are monoclonal tumors arising in the myometrium, and are the most common tumor of reproductive age women. An increasing body of evidence supports the hypothesis that UFs originate from aberrant stem cells in the myometrium. We have now identified a Stro-1+/CD44+ myometrial stem cell (MSC) capable of self-renewal and regeneration of myometrial tissues, which gives rise to UFs in animal models. With our ability to identify and isolate these MSCs, we are in a unique position to address how risk factors impact the UF cell-of-origin to initiate and promote the development of these tumors. Like many diseases, there is ample evidence that both environmental exposures and genetic alterations contribute to UF pathogenesis. We, and others have shown that early life environmental exposures to endocrine disrupting compounds (EDCs) increase UF risk by inducing developmental reprogramming of the epigenome. Such epigenomic reprogramming involves changes in histone and DNA methylation patterns that alter chromatin architecture and gene transcription, and when induced in early life, persist into adulthood. Genetic alterations in mediator 12 (MED12) and the tuberous sclerosis complex 2 (TSC2) tumor suppressor, drive development of UF tumors in both humans and rodent models, respectively. Interestingly, MED12 and TSC2 defects share a common downstream effector: activation of β-catenin signaling and TCF/LEF transactivation of gene expression. Our previous inability to interrogate the cells-of-origin for UFs has limited our understanding of how gene:environment interactions (GxE) influence UF risk. Now that we can isolate and profile MSCs, we are for the first time in a position to overcome this critical barrier to understanding determinants of risk for this important disease. In this application we will utilize our new-found ability to isolate and interrogate MSCs, and apply recent insights on how environmental exposures reprogram the epigenome, to explore GxE interactions that promote tumorigenesis in the cell-of-origin for UFs. Specific Aim 1: Test the hypothesis that activation of β-catenin signaling is a common effector pathway for genetic alterations that drive UFs. In this mechanistic Aim, we will test the hypothesis that in MSCs, MED12 mutation (human) or loss of Tsc2 (rat) results in an altered transcriptional profile characterized by increased TCF/LEF transactivation of gene expression. Specific Aim 2: Test the hypothesis that developmental EDC exposure results in epigenetic reprogramming that cooperates with genetic defects in MSC/TICs. In this mechanistic Aim, we will characterize EDC-induced reprogramming of the epigenome, and test the hypothesis that reprogramming of TCF/LEF target genes exacerbates their expression when β-catenin is activated in rMSCs and in tumor initiating cells (TICs). Specific Aim 3: Test the hypothesis that MSCs associated with high vs low UF risk exhibit differences in epigenetic histone modifications. In this translational Aim, we will explore the relationship between MSC epigenetic patterns and UF risk using MSCs isolated from normal myometrium of women without UFs (MyoN) and at-risk myometrium from women with UFs (MyoF). Because epigenomic alterations are potentially reversable, we will also test the hypothesis that an intervention that reduces UF risk does so by decreasing MSC number and/or “resetting” the MSC epigenome back to a low risk profile. Impact: Our work address several knowledge gaps and priority research areas as defined by NIH including; Stem/Progenitor Cells in Gynecologic Health and Disease, Transdisciplinary Research and '–Omics' in Gynecologic Disorders. Importantly, it will also be the first exploration of GxE interactions that drive disease in the cells of origin for UFs.
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Publications See publications associated with this Grant.
Program Officer Kimberly Mcallister
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