Translatome analysis reveals microglia and astrocytes to be distinct regulators of inflammation in the hyperacute and acute phases after stroke
Abstract/Contents
- Abstract
- Ischemic stroke is a leading cause of death and long-term disability. Neuroin-flammation after stroke can significantly affect stroke outcomes¬--it can clear dead tissue and aid neuroplasticity but also exacerbate cell death. However, the exact astrocytic and microglial signaling pathways initiating neuroinflammation after stroke are unresolved and will be critical for developing immunomodulatory stroke therapies. In Chapter 1, I give background on the progression of stroke, status quo of treatments, and the genetic tools used to profile gene expression changes in microglia and astrocytes. Furthermore, I lay out the key gaps in knowledge and give an overview of how this dissertation fills those gaps. In Chapter 2, to parse the astrocytic and microglial response from that of infil-trating cells in the brain after stroke, we used the RiboTag technique to separately obtain astrocyte and microglia-derived transcriptional responses. By crossing floxed RiboTag mice with Aldh1l1-CreER or Cx3cr1-CreER mice, we tagged astrocytic or microglial ribo-somes, respectively, and then isolated cell-specific mRNA from ribosomes immunopre-cipitated from brain tissue. We performed RNA-sequencing on astrocyte or microglia-specific transcripts obtained from peri-stroke cortex in male and female mice 4 hours and 3 days after distal middle cerebral artery occlusion or sham surgery. Few sex differences were observed. Microglia initiated a rapid response to stroke at 4 hours by adopting a proinflammatory profile associated with the recruitment of immune cells while the astro-cyte profile was dominated by stress response, as well as proinflammatory genes. By 3 days, microglia have dampened their inflammatory response in exchange for a prolifera-tive, phagocytic state. At this timepoint, astrocytes have enhanced their pro-inflammatory response and may be doing this through transcriptional regulation. Taken together this data comprehensively describes the astrocyte and microglia-specific translatome re-sponse in the hyperacute and acute period after stroke and identifies pathways critical for initiating neuroinflammation. Chapter 3 summarizes the findings, provides additional discussion, and comments on future directions to be taken.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Hernandez, Victoria Guadalupe |
|---|---|
| Degree supervisor | Buckwalter, Marion |
| Degree supervisor | Wyss-Coray, Anton |
| Thesis advisor | Buckwalter, Marion |
| Thesis advisor | Wyss-Coray, Anton |
| Thesis advisor | Gentles, Andrew J |
| Thesis advisor | Kaltschmidt, Julia |
| Degree committee member | Gentles, Andrew J |
| Degree committee member | Kaltschmidt, Julia |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Neurosciences Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Victoria Guadalupe Hernandez. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/mb308pj9319 |
Access conditions
- Copyright
- © 2023 by Victoria Guadalupe Hernandez
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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