Cell state transitions mediated by epigenetic remodeling and transcriptome reprogramming are fundamental to many biological processes, including stem cell differentiation, cancer cell adaptive resistance development, immune cell activation, etc. In our parent U01 grant, we have developed an analytical framework to resolve the key regulators of the dynamic cell state changes associated with such transitions in cancer through a strategic orchestration of information-theoretic approaches, time-resolved multi-omics characterization, and single-cell analytics. Here, we propose to extend this method to analyze the state transition of two important cell types that play critical roles in the regulation of Alzheimer?s disease (AD) pathology. Genetic associations with increased risk for AD implicate both innate immune processes and microglial cells, and suggest that environmental factors, such as infection, may play a role in AD. Chronic infection of neurotropic herpesviruses, particularly HSV-1, has been found to contribute to the development of AD pathology. Activation of astrocytes and microglia upon such chronic infection have both neuroprotective and neurotoxic effects on AD. Astrocytes and microglia appear to mutually coordinate their activation in a pro-amyloidogenesis feed-forward loop, where ?-amyloid plaques induce astrocyte secretion of C3, followed by a C3aR-dependent reduction of microglial phagocytosis. Additionally, microglia can also trigger A1 reactive astrocytes by releasing fragmented mitochondria, or the pro-inflammatory cytokines Il-1?, TNF? and C1q13, resulting in neuronal loss in AD. In a nutshell, this heterogeneous microenvironment of AD is comprised of a dynamic composition of cell types and states, reminiscent, in a physical sense, of an evolving tumor microenvironment. The evolving transcriptional and epigenetic programs lead to functional alterations that contribute to AD pathogenesis. Attention to these non-neuronal cell types has arisen in attempt to more holistically understand the disease and highlight novel therapeutic avenues. Our hypothesis is that time-resolved multi-omics and single-cell characterizations, coupled with information theory approaches that can integrate such kinetic data into a single self-consistent model can help resolve AD?s physiopathology. We propose to leverage the information theory-based analytical framework we have developed within our parent U01 project as well as a novel neurotropic herpesvirus infection amyloid mouse model to investigate the dynamic cell state changes of astrocytes and microglia and their interplay in an HSV-1 infection model of AD pathology. This admin supplement program would allow us to extend our methodologies to address AD, with two goals. First, we will improve our understanding of the role of microglia and astrocytes in the regulation of AD pathology. Second, and similar to what we have found in our tumor biology work, we may also reveal new avenues for therapeutic intervention.

Public Health Relevance

Increasing evidence supports the role of chronic infection of neurotropic viruses, such as HSV-1, in the development of Alzheimer?s disease (AD) pathology. Dynamic cell state transitions in cell types associated with innate immunity and neuronal support of the central nervous system, including microglia and astrocytes, play critical roles in this process and may be resolved by a longitudinal multi-omics and single-cell characterization, coupled with information theory analysis. The results will provide key molecular connections between the rational microglial and astrocytic responses to HSV-1 infection and AD, opening new avenues for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1)
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Hughes, Shannon K
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Institute for Systems Biology
United States
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