The role of VCP and small molecule activators of VCP on the degradation of diverse protein structures
Active Project Grant Awarded Last action
- Award ID
- F30AG099358
- 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
- $55,114
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
- Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and numerous other fatal and incurable neurodegenerative diseases present with protein aggregates. The presence of aggregates indicates altered protein homeostasis, potentially due to decreased protein degradation. As these aggregates are linked to disease progression and severity, enhanced degradation of these aggregates could be a potential therapeutic strategy for neurodegenerative diseases. However, there remain critical gaps in knowledge about how protein homeostasis is altered in neurodegenerative diseases. Our lab identified a key player of protein homeostasis and aggregate degradation, valosin containing protein (VCP), a AAA+ atpase that extracts and unfolds polyubiquitinated proteins, including proteins in aggregates, for proteasomal degradation. VCP has also been linked to multiple neurodegenerative diseases, including ALS and FTD. These findings suggest that VCP-dependent protein degradation may be altered in neurodegenerative diseases and could be potentially therapeutically targeted by pharmacologic VCP modulators. To harness VCP function to remove aggregates, this project will determine how VCP kinetics change with protein structure changes observed in neurodegenerative diseases. We hypothesize that VCP substrate structure affects VCP-dependent protein degradation such that VCP kinetics are rate limiting when proteins oligomerize or aggregate. To test this hypothesis, this project will use confocal microscopy, flow cytometry, and biochemical assays to compare VCP-dependent degradation of diffusely expressed proteins with that of soluble oligomers in cells for aim 1, and with insoluble aggregates in cells for aim 2. The completion of these aims will provide new insights into how VCP processes protein oligomers and aggregates, which will shed light on how a key regulator of protein homeostasis is impacted by changes in protein structure observed in neurodegenerative diseases. Additionally, these aims will help assess the potential of pharmacologic VCP modulators to enhance protein aggregate degradation, which could potentially establish a new avenue of treatment for the diseases that harbor these aggregates. This research training plan will be carried out at the university of pennsylvania, home to one of the leading neurodegenerative disease research programs in the nation, under the mentorship of DR. Edward LEE, a renowned physician-scientist dedicated to the understanding and treatment of these diseases. Through this plan, the trainee will develop expertise in protein homeostasis mechanisms and the application of induced pluripotent stem cell-derived neurons to advance mechanistic and therapeutic insights for neurodegenerative diseases. With the integration of research, clinical training, and professional development, this plan will equip the trainee with the knowledge, skills, and experience to grow into the physician-scientist they aspire to be.
Quick answers
Who received award F30AG099358?
F30AG099358 was awarded to The Trustees Of The University Of Pennsylvania by National Institute on Aging (National Institutes of Health) on November 25, 2026.
How much is award F30AG099358 worth?
$55,114 has been obligated on F30AG099358.
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