Microglia contribution to disease pathogenesis in C9ORF72 ALS/FTD
Active Project Grant Awarded Last action
- Award ID
- R01NS120331
- Recipient
-
Dignity Health UEI SKX6AXF9ZTM3 Part of Commonspirit Health
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $6,977,040
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 86% complete
- Originally
- Funding
-
- $6,287,213.00 Federal
- $689,827.00 Non-federal
- Place of performance
- Phoenix, AZ 85013, USA
Award details come from USAspending.gov.
Description
- Abstract
- The role of microglia in the C9ORF72 (C9) amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD) disease spectrum remains poorly understood. Early investigations found that microglia activation was significantly higher in ALS with dementia and impaired executive function, suggesting that microglia activation correlates with FTD-like symptoms in ALS. More recent neuropathologic examinations of microglia in ftld patient autopsy brains with mutations in progranulin versus C9ORF72 concluded that the observed microglia dysfunction was different between the two genetically different patient subgroups suggesting specificity of microglia dysfunction depending on the etiology of the patient population. One interesting aspect of microglia- neuron communication is the role of microglia in the maintenance and refinement of synaptic networks through the selective pruning of synapses, which occurs predominantly during development but has been shown to also be triggered in alzheimer's disease (ad) and related dementias, including FTD. The degree of synapse loss in ad strongly correlates with cognitive decline, even more than the amount of plaque, tangles or neuronal loss, and a recent study of ALS postmortem tissue confirmed increased synapse loss in the prefrontal cortex of patients with reported cognitive impairments. Our laboratory has preliminary data supporting the hypothesis that there is an altered neural-immune interaction in the cortical forebrain regions of C9ORF72 patients with confirmed FTD in which microglia and neurons modify each other's function. Using patient-derived hipsc microglia and cortical neurons, we are able to show that C9 patient-derived hipsc microglia mono-cultures do have intrinsic phenotypes, including altered gene profiles, phagocytic activities and lysosomal function. Most interestingly, preliminary data suggests that C9 microglia do regulate neuronal excitability and survival of C9 ipsc neurons. To further investigate the role and contribution of microglia in C9 cortical degeneration, we propose to thoroughly investigate the intrinsic properties of C9 hipsc-microglia (from all patient subgroups: FTD, FTD/ALS, ALS; AIM1). For the first time, we will then CO-culture these microglia with C9 and healthy control hipsc cortical neurons to better understand the CO-regulation between these two cell types (aim 2). Finally, in the third aim, we will study microglia activation and pathology in C9 patient postmortem autopsy tissue. This will include cell-type specific genetic profiling from existing snrna SEQ data sets, immunohistochemistry of microgliosis and multi-label immunostaining for microglial-specific candidate genes/proteins in conjunction with C9 neuronal disease pathology markers (TDP-43 and C9 dprs) to gain novel knowledge on whether microglia are preferentially altered in close vicinity to neuronal pathologies.
Transactions
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| Original award | $689,827 | $689,827 |
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Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Mayo Clinic Jacksonville (A Nonprofit Corporation) | $122,563 | |
| The Translational Genomics Research Institute | $1,618,800 | |
| University Of Southern California | $402,500 |
Quick answers
Who received award R01NS120331?
R01NS120331 was awarded to Dignity Health by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 1, 2021.
How much is award R01NS120331 worth?
$6,977,040 has been obligated on R01NS120331: $6,287,213 in federal funding and $689,827 in non-federal funding.
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