Microglial lipid droplet accumulation perpetuates neuroinflammation and neurodegeneration in alpha-synucleinopathies
Active Project Grant Awarded Last action
- Award ID
- F32AG101853
- Recipient
-
Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University UEI M5QFLTCTSQN6
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $76,780
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 0% complete
- Place of performance
- Cleveland, OH 44195, USA
Award details come from USAspending.gov.
Description
- Abstract
- Αsynucleinopathies are age-related, progressive neurodegenerative diseases characterized by the presence of proteinaceous inclusions primarily comprised of misfolded αsynuclein (ΑSYN). These diseases encompass dementia with lewy bodies (DLB), parkinson's disease (PD), and a subset of alzheimer's disease cases with lewy body pathology. Neuron-released protein aggregates can engage innate immune pathway activation leading to chronic neuroinflammation, implicated in the pathophysiology of αsynucleinopathies. An emerging area of research in neuroinflammation is intracellular accumulation of lipid droplets (LDS) in glial cells. LDS are monolayer membrane bound organelles that store excess lipids. In ad, AΒ plaques trigger microglial LD accumulation resulting in transcriptomic alterations skewing microglia towards a hyperinflammatory state, reducing debris clearance, and increased generation of reactive oxygen species (ROS). The role of microglial LD accumulation in αsynucleinopathies remains undercharacterized. Our preliminary data suggests that ΑSYN aggregates induce microglial LD accumulation in DLB, reducing phagocytic capacity and increasing LD:mitochondria contacts. The overarching goal of this proposal is to elucidate the pathological role of microglial LDS in contributing to propagation of neuroinflammation and subsequent neurodegeneration. We also seek to explore the mechanisms by which LDS impact mitochondrial function and phagocytic capacity. In aim 1, I will perform a series of experiments including real-time monitoring of ΑSYN aggregate clearance by lipid-laden microglia, evaluation of mitochondrial dynamics via seahorse metabolic assays, and evaluate how LD inhibition modifies disease progression in ΑSYN-PFF injected mice. These studies will be performed in the lab of my CO-mentors, DR. Justin lathia (mitochondrial metabolism assays) and DR. Dimitrios davalos (LD inhibitor in vivo study). In the second aim, I will measure lipid load (through LD staining), mitochondrial function (seahorse metabolic assays), and disease progression (via assessment of neuronal death, gliosis, and motor deficit analyses) in ΑSYN-PFF injected microglial-specific inflammasome-deficient mice. These experiments will be performed under the supervision of DR. Nikhil panicker, my primary mentor, who has significant expertise in inflammasome biology in αsynucleinopathies. Together, this project will provide valuable insight into an undercharacterized mechanism driving neuroinflammation and the training I will receive during this award will serve as the inceptive step in establishing an independent research career in neurodegeneration.
Quick answers
Who received award F32AG101853?
F32AG101853 was awarded to Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University by National Institute on Aging (National Institutes of Health) on December 26, 2026.
How much is award F32AG101853 worth?
$76,780 has been obligated on F32AG101853.
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