Regulation of sphingolipid biosynthesis and motor neuron disease
Active Project Grant Awarded Last action
- Award ID
- R01NS138167
- Recipient
-
The Johns Hopkins University UEI FTMTDMBR29C7
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,177,600
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 26% complete
- Place of performance
- Baltimore, MD 21205, USA
Award details come from USAspending.gov.
Description
- Abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative disease of the upper and lower motor neurons. ALS is a clinically and biologically heterogeneous disease and includes sporadic and genetic forms. Several cellular mechanisms have been linked to neurodegeneration in ALS, but few metabolic causes of the disease have been comprehensively studied. Disruptions in lipid metabolism pathways have recently been linked to neurodegeneration in ALS, making IT an emerging area of inquiry. We and others have recently discovered and reported a distinct class of mutations in the enzyme serine palmitoyltransferase (SPT) that cause a monogenic form of juvenile ALS. Sphingolipids are a subgroup of lipids that serve as components of cell membranes and organelles, as well as potent signaling molecules. SPT catalyzes the first step in sphingolipid biosynthesis and its activity is closely regulated to meet cellular demands but avoid accumulation of excess sphingolipids. We have shown that the SPT-related ALS mutations are gain-of-function variants that disrupt the ormdl/ceramide- mediated inhibition of SPT and thus result in unrestrained SPT activity. However, how excess sphingolipid synthesis causes motor neuron degeneration is not clearly delineated. We have established cellular models of this disease in patient fibroblasts as well as ipscs. We have also obtained knock-in mouse models of SPT- related ALS. Our preliminary studies show that our models of the disease recapitulate SPT overactivity. They also show that the SPT-related mutations result in mitochondrial bioenergetics dysfunction and morphological abnormalities in human cell models of the disease. In addition, we have shown increased ceramide content in mitochondria of SPT-related ALS cell models. Together, these findings prompted US to hypothesize that increased SPT activity results in increased mitochondrial ceramide content and mitochondrial dysfunction, which in turn leads to neurodegeneration. In this application, we propose to test this hypothesis. In specific aim 1, we will evaluate mitochondrial bioenergetics, morphology, mitophagy flux, and mitochondrial cell death pathways in SPT-related ALS patient cells. We will also measure the sphingolipid content of isolated mitochondria in our cell models. In specific aim 2, we will evaluate mitochondrial dysfunction in mouse tissues and primary cell cultures of the mouse nervous system. In addition, we will use CO-culture systems to assess if myelinating glia contribute to motor neuron degeneration in SPT-related ALS. In specific aim 3, we will evaluate the efficacy of anti-sense oligonucleotides that reduce SPT activity in restoring normal mitochondrial function and motor neuron dysfunction in human cells and mouse models of the disease. Together, the studies proposed in this application will advance our understanding of underlying metabolic pathomechanisms of neurodegeneration caused by dysregulation of sphingolipid biosynthesis and enable future therapeutic strategies that target this pathway.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $585,367 | |
| Original award | $592,233 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | $336,488 |
Quick answers
Who received award R01NS138167?
R01NS138167 was awarded to The Johns Hopkins University by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on August 1, 2025.
How much is award R01NS138167 worth?
$1,177,600 has been obligated on R01NS138167.
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