Aging exacerbates neutrophil persistence and negatively impacts stroke outcomes
Ended Project Grant Awarded Last action
- Award ID
- R21AG086751
- Recipient
-
Northwestern University UEI KG76WYENL5K1
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $440,000
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Place of performance
- Chicago, IL 60611, USA
Award details come from USAspending.gov.
Description
- Abstract
- Stroke is a major cause of disability in the U.S., disproportionately impacting older adults. Ischemic stroke accounts for over 75% of stroke subtypes, but the only approved treatments rely on blood flow restoration (reperfusion). Significant gains made in acute stroke treatments have increased the number of patients undergoing acute reperfusion treatment. Despite successful reperfusion, most patients still suffer from post-stroke disability, driven in part by ischemia/reperfusion (i/r) injury. Activation of the inflammatory response following ischemic stroke is known to cause further neurologic injury, and impairs recovery. Neutrophils are the initial cell type involved in this inflammatory response, however our understanding of neutrophil- mediated brain injury following ischemic stroke is lacking. Therapeutic advancements for i/r injury are unlikely without better understanding the neutrophil-mediated injury following ischemic stroke. By leveraging publicly available gene expression datasets, we found a potentially critical transcription factor, nuclear receptor NR4A2, was upregulated in neutrophils. NR4A2 is widely expressed in several types of leukocytes, but universally serves as a regulator of lifespan and longevity. NR4A2 is also upregulated in circulating neutrophils in aged mice and humans, suggesting that neutrophils from older adults may persist once entering the ischemic brain. We hypothesize that 1.) neutrophils persist in the ischemic brain following i/r in aged brains compared to younger brains due to increased neutrophil NR4A2 expression, and 2.) increased NR4A2 expression in recruited neutrophils contribute to impaired neutrophil function and increased injury following ischemic stroke, leading to worse outcomes. Aim 1 will focus on how NR4A2 affects the spatiotemporal recruitment and persistence of neutrophils following ischemic stroke. Aim 2 will determine how NR4A2 impacts neutrophil function and overall outcomes following ischemic stroke. These aims will be tested using a murine transient middle cerebral artery occlusion model with young and aged wild-type C57BL/6 catchup mice crossed with NR4A2 knockout mice. The proposed studies will fill an important knowledge GAP regarding the neutrophil-response following acute i/r and address the discrepancy in this response in aged brains. Findings from these studies will inform development of novel therapies targeting neutrophil-mediated mechanisms of brain injury. The proposed study has the potential for expanding treatment approaches for ischemic stroke beyond blood flow restoration and has broad potential translation to other aging-related brain disorders.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Original award | $440,000 |
Quick answers
Who received award R21AG086751?
R21AG086751 was awarded to Northwestern University by National Institute on Aging (National Institutes of Health) on May 15, 2024.
How much is award R21AG086751 worth?
$440,000 has been obligated on R21AG086751.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award