EAGER: AIR-NCS Novel epigenetic assay to probe neural stem cell fate in neurodegenerative environment

University Of Maryland Baltimore County, Baltimore MD

Investigators

Abstract

Overview: This EAGER proposal responds to the Accelerating Integrative Research in Neuroscience and Cognitive Science (AIR-NCS) initiative. This proposal seeks to develop novel tools that can be used to examine how neurodegenerative environments lead to epigenetic changes in neural stem cells, which then impact patterns of differentiation and ultimately affect how the brain adapts and responds to the neurodegenerative environment. This proposal responds specifically to the thematic area "adaptation to changing environments". The work combined bioengineering (development of a novel epigenetic assay) with neuroscience and developmental biology (examining how the neurodegenerative environment impacts neural stem cell fate), and should impact areas of neuroregeneration of interest to the Biomedical Engineering Program. The proposed work is appropriate for an EAGER mechanism as it is exploratory, based on a new, unproven hypothesis, but if successful, could lead to new transformational discoveries at the interface between engineering and neuroscience. Intellectual Merit: The process of neural stem cell differentiation into different neuronal and glial phenotypes requires the complex interplay between programs associated with gene silencing and or activation. DNA methylation of promoter regions of certain genes is one mechanism by which gene expression is dynamically regulated. It is hypothesized that certain neurodegenerative environments induce epigenetic changes in neural stem cells, leading to changes in cell proliferation and/or differentiation, which contributes to the disease phenotype and limit the neuroregenerative potential of stem cell therapies. Specifically, it is hypothesized that a model neurodegenerative (Alzheimer's like) environment associated with high oxidative stress and the presence of beta-amyloid will lead to changes in DNA methylation of promoters associated with either the SMAD or JAK/STAT pathways, leading to changes in neural stem cell fate such as a shift away from neurogenesis and towards the formation of reactive astrocytes. To test this novel hypothesis, it is proposed (1) to develop a novel tool to rapidly and inexpensively probe epigenetic changes in cultured cells in response to an environmental stimulus; (2) to use the new tool to examine epigenetic changes in neural stem cells in response to a model neurodegenerative (Alzheimer's like) environment; and (3) to assess how epigenetic changes are liked to changes in neural stem cell differentiation, and how that impacts the neuroregenerative potential of stem cell therapies. While the ultimate goal is to address all of these goals, with funding for one year requested from this EAGER, the work planned will be focused on the development of the novel tool for rapidly probing epigenetic changes in cells and then address the feasibility of using the tool in neural stem cells. This work will contribute to the understanding of how different environments affect stem cell differentiation, and the role of epigenetics in cellular response to the environment. Broader Impacts: The proposed work will eventually assist in the development of neuroregenerative strategies based on stem cells. A novel tool for rapidly and inexpensively examining epigenetic changes in neural stem cells and stem cell differentiation could also be used to examine epigenetic changes associated with cancer or other diseases. The epigenetic assay is based on thermodynamic principles, and will be used as an example in a core course in the chemical engineering curriculum at UMBC as well as the bioengineering laboratory taught by the PI. One undergraduate researcher and one graduate student will work on the project and receive training in an interdisciplinary environment.