The role of neutrophil heterogeneity and molecular mechanisms in driving ALS
Ended Project Grant Awarded Last action
- Award ID
- F31NS139629
- Recipient
-
Regents Of The University Of Michigan UEI GNJ7BBP73WE9
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $129,717
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date
- Place of performance
- Ann Arbor, MI 48109, USA
Award details come from USAspending.gov.
Description
- Abstract
- There is overwhelming evidence that the immune system plays a significant role in amyotrophic lateral sclerosis (ALS) pathogenesis. However, information about the role of specific immune populations and the underlying mechanisms is currently lacking. Neutrophils are innate immune cells that function as first- responders to damage, including damage to neuronal tissue. These cells ultimately determine whether damaged neurons undergo repair or whether damage is exacerbated. Additional damage can occur directly via cytotoxicity or indirectly through the recruitment of other immune cell types, the release of pro-inflammatory cytokines, and the suppression of repair mechanisms. Thus, neutrophils may play a central role in the response to motor neuron damage in ALS. To support this, our previously published studies show that neutrophils are increased in the blood of ALS patients, that these cells accumulate in the central nervous system (CNS) of individuals with ALS, and that increased levels in the peripheral blood are associated with shortened survival. In addition, preliminary data show that peripheral neutrophils are dysregulated in ALS with increased expression of trafficking and activation markers. Finally, our predictive models of disease show that neutrophil levels are the single best predictor of future ALS progression in patients. Therefore, i hypothesize that neutrophils contribute to ALS pathology by accelerating motor neuron death and by suppressing pro-repair immune responses in the CNS. To test this, i propose two specific aims which will assess the role of neutrophils in ALS. In the first aim, i will identify subpopulations of neutrophils or neutrophil-based mechanisms that are associated with ALS progression and survival. To do this, i will use flow cytometry, single cell RNA- SEQ (scrna-SEQ), and analysis of neutrophil extracellular trap (net) remnants to immunophenotype neutrophils in the peripheral blood of control and ALS participants. Dysregulated pathways will first be identified and then associated with ALS progression and survival using our existing biostatistical pipeline. In the second aim, i will identify the mechanisms by which neutrophils become activated and more pro- inflammatory in ALS. To do so, i will culture primary and ipsc-derived neutrophils with and without ALS- associated proteins such as TDP-43 aggregates. Activation and pro-inflammatory activity will be determined via flow cytometry and assays for degranulation, reactive oxygen species release, and net formation. Overall, completion of these studies will elucidate mechanisms driving neutrophil-mediated damage in ALS and identify potential therapeutic targets for future studies.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $43,615 | |
| Amendment | $43,051 | |
| Amendment | $0 | |
| Original award | $43,051 |
Quick answers
Who received award F31NS139629?
F31NS139629 was awarded to Regents Of The University Of Michigan by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on January 20, 2025.
How much is award F31NS139629 worth?
$129,717 has been obligated on F31NS139629.
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