ACSS2 metabolic-epigenetic axis in microglia development and activity
Active Project Grant Awarded Last action
- Award ID
- F32AG092205
- Recipient
-
The Trustees Of The University Of Pennsylvania UEI GM1XX56LEP58
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $79,348
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 0% complete
- Place of performance
- Philadelphia, PA 19104, USA
Award details come from USAspending.gov.
Description
- Abstract
- Microglia are the phagocytic immune cells of the central nervous system. While the transcription factors have been identified for the coordination of microglia development and activation potential in the brain, how metabolism-driven epigenetic modifications govern microglia physiology remains unknown. IT has been previously shown that acetate, through the GUT microbiota, controls maturation of microglia within the brain, however, the molecular mechanism underlying this phenomenon has not been investigated. Furthermore, IT has been demonstrated that ACSS2 suppresses inflammatory responses in microglia. In the present study, we discovered acetyl-COA synthetase 2 (ACSS2), which generates acetyl-COA from acetate, dictates microglia development and regulates activation potential. While many metabolic proteins are localized to either the cytoplasm or mitochondria to assist in the generation of energy, I found ACSS2 expressed solely in the nucleus of microglia, like neurons. However, in ACSS2 knockout microglia, there is significant loss of cell cycle progression and anti-inflammatory gene signatures. This results in significant decreases in microglia abundance within the brain and inflammatory phenotypes in ACSS2KO mice. These findings underscore the remarkable role of ACSS2 for microglia function. Therefore, we hypothesize ACSS2 utilizes acetate to generate local pools of acetyl-COA directly in the nucleus, allowing for histone acetylation, and resultant upregulation of key cell cycle and anti-inflammatory genes necessary for microglia development and immune suppression, respectively. I will evaluate how ACSS2 orchestrates microglia development through (1) use of rnaseq and histone mass spectrometry during microglia development and a mouse aging paradigm, (2) transplant macrophages harboring point mutations in ACSS2 into mice which lack microglia to determine the functional residues necessary for ACSS2-mediated microglia development, and (3) employ an antibody-based proximity ligation method of ACSS2 to determine which proteins ACSS2 interacts with in primary murine microglia. These experiments will demonstrate that ACSS2 is required for proper microglia development, highlight how ACSS2 epigenetically programs cells for development, and unveil which functions of ACSS2 are required for this development. Furthermore, I will investigate how ACSS2 driven anti-inflammatory processes are epigenetically programmed in microglia through (1) development of a microglia specific ACSS2 deletion mouse model and multi-cytokine profiling and (2) utilize microglia depletion and macrophage transplantation in aged and alzheimer's disease mice to determine if ACSS2 overexpressing macrophages increases cognitive ability. With microglia-targeted therapeutics and macrophage transplantation demonstrating improved cognition in multiple neuroinflammatory diseases, these experiments will further show that ACSS2 holds tremendous therapeutic potential, especially in microglia-driven neuroinflammatory diseases.
Quick answers
Who received award F32AG092205?
F32AG092205 was awarded to The Trustees Of The University Of Pennsylvania by National Institute on Aging (National Institutes of Health) on December 4, 2026.
How much is award F32AG092205 worth?
$79,348 has been obligated on F32AG092205.
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