Lineage and functional consequences of clonally expanded microglia in ad brain
Active Project Grant Awarded Last action
- Award ID
- F30AG099333
- Recipient
-
President And Fellows Of Harvard College UEI JDLVAVGYJQ21 Part of Harvard College President & Fellows Of
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $86,648
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 0% complete
- Originally
- Place of performance
- Boston, MA 02115, USA
Award details come from USAspending.gov.
Description
- Abstract
- Alzheimer's disease (ad) is the most common form of neurodegenerative dementia. Research in the last two decades has revealed that microglia, the innate immune cells of the brain, have important roles in modulating ad PATHOPHYSIOLOGY1. Experimental evidence demonstrates that microglia have both deleterious and protective functions: they phagocytose amyloid-beta, but when activated, produce neurotoxic molecules that can worsen the neurodegenerative CASCADE2. While microglia are the predominant myeloid cell population in the brain, there is emerging evidence that other brain myeloid cell types can also influence ad pathology. Most notably, blood monocyte derived macrophages (MDM) behave similarly to activated microglia when recruited to the brain by inflammatory signals. Both microglia and mdms, like all cells, acquire somatic mutations with age. Our lab has observed that brains affected by ad are more likely to harbor microglia-like cells that have acquired mutations in cancer driver genes and clonally expanded. Although these mutant cells exhibit a microglial transcriptional profile, the phenotypic overlap between microglia and activated mdms prevents definitively determining that these mutants are "bona fide" microglia, which are generally defined as originating from the embryonic yolk SAC3. Our preliminary data shows that driver mutations observed in these microglia-like cells were also found in each patient's matched blood, suggesting our hypothesis that some mutant microglia represent blood mdms that have replaced the existing microglia, altering immune responses in the brain. To test our hypothesis, we will first use highly sensitive sequencing to detect somatic mutations in cancer driver genes in paired blood and brain samples from ad patients and age matched controls. We will analyze the resulting data to identify patterns of shared mutations between the brain and blood to explore the degree to which MDM infiltration occurs and genetic factors that may affect this process (aim 1). We will utilize this methodology to profile samples collected across the brain, including regions both commonly affected and spared by ad, to test whether ad pathology can vacate a niche for clonal expansion of mutant microglia-like cells (aim 2). Finally, we will assess the functional impact of mutant microglia in the brain using epigenomic profiling to understand the consequences of mutations for brain physiology (aim 3). Together, I aim to characterize how the clonal genetic architecture of microglia changes under the pressures of aging and inflammation to further our understanding of immune contribution to neurodegeneration while delineating risk factors that may be detectable and potentially intervenable in blood.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $43,324 | |
| Amendment | $0 | |
| Original award | $43,324 |
Quick answers
Who received award F30AG099333?
F30AG099333 was awarded to President And Fellows Of Harvard College by National Institute on Aging (National Institutes of Health) on November 29, 2026.
How much is award F30AG099333 worth?
$86,648 has been obligated on F30AG099333.
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