Functional interrogation of region-specific reactive astrocyte factors in neuroinflammation
Ended Project Grant Awarded Last action
- Award ID
- F31NS135948
- Recipient
-
New York University UEI M5SZJ6VHUHN8
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $168,455
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date
- Place of performance
- New York, NY 10016, USA
Award details come from USAspending.gov.
Description
- Abstract
- Once thought to be immunologically privileged except in disease, the central nervous system (CNS) is now understood to interact closely with the immune system even in the absence of pathology. Astrocytes, the most abundant CNS glial cell, are key mediators of brain-immune cross-talk, interacting closely with microglia, forming the glial limitans interfacing with and regulating the blood-brain barrier, and recruiting peripheral immune cells into the CNS via the secretion of chemokines in disease. In response to CNS inflammation, astrocytes undergo dramatic transcriptional and functional changes - a response termed 'astrocyte reactivity'. Reactive astrocytes are a common feature of nearly all injury and disease in the nervous system, yet our understanding of the role of these cells in the pathogenesis of disease remains limited. Continually emerging evidence has shown that astrocytes consist of heterogeneous subpopulations that vary greatly across different regions of the brain; however, inflammatory astrocyte reactivity is still widely viewed as a homogeneous response. To explore heterogeneity in reactive astrocyte responses to inflammation, i have performed paired single-nucleus RNA and atac sequencing of astrocytes from mice injected with the bacterial endotoxin lipopolysaccharide (LPS), producing acute neuroinflammation and astrocyte reactivity. By profiling astrocytes across the whole forebrain, i identified that, in the early phase of the inflammatory response, telencephalic reactive astrocytes highly express hepatocyte growth factor (HGF), a secreted factor with anti-inflammatory properties in peripheral tissues. In contrast, diencephalic reactive astrocytes produced 15-hydroxyprostaglandin dehydrogenase (hpgd), the enzyme responsible for degradation of the inflammatory eicosanoid prostaglandin E2 (PGE2). The goal of this proposal is to investigate the role of region-specific reactive astrocyte expression of HGF and hpgd in the progression of neuroinflammation. Given HGF expression has been previously described as attenuating inflammatory cytokine production by peripheral immune cells, i hypothesize that telencephalic reactive astrocyte HGF inhibits microglial reactivity, reducing the production of inflammatory cytokines and suppressing neuroinflammation. To test this hypothesis, experiments in aim 1 will assess the effect of HGF on microglial reactivity in vitro and in vivo using astrocyte-specific HGF conditional knockout mice following LPS injection. As hypothalamic PGE2-responsive neurons have been implicated in altered body temperature and anorexia during neuroinflammation, aim 2 will explore the effects of reactive astrocyte hpgd expression on the abundance of PGE2 in the diencephalon, body temperature, and sickness behaviors following LPS injection in astrocyte- specific hpgd conditional knockout mice. Together, these experiments will provide novel characterization of the functional roles of two region-specific reactive astrocyte factors which may affect the pathophysiology of neuroinflammation, identifying new mechanisms which would contribute to many neurological diseases.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $42,737 | |
| Amendment | $41,906 | |
| Amendment | $41,906 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $41,906 |
Quick answers
Who received award F31NS135948?
F31NS135948 was awarded to New York University by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on January 15, 2025.
How much is award F31NS135948 worth?
$168,455 has been obligated on F31NS135948.
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