
NSF Org: |
IOS Division Of Integrative Organismal Systems |
Recipient: |
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Initial Amendment Date: | June 28, 2023 |
Latest Amendment Date: | June 28, 2023 |
Award Number: | 2324378 |
Award Instrument: | Standard Grant |
Program Manager: |
Anna Allen
akallen@nsf.gov (703)292-8011 IOS Division Of Integrative Organismal Systems BIO Directorate for Biological Sciences |
Start Date: | October 15, 2023 |
End Date: | September 30, 2026 (Estimated) |
Total Intended Award Amount: | $775,000.00 |
Total Awarded Amount to Date: | $775,000.00 |
Funds Obligated to Date: |
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History of Investigator: |
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Recipient Sponsored Research Office: |
105 JESSUP HALL IOWA CITY IA US 52242-1316 (319)335-2123 |
Sponsor Congressional District: |
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Primary Place of Performance: |
105 JESSUP HALL IOWA CITY IA US 52242-1316 |
Primary Place of
Performance Congressional District: |
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Unique Entity Identifier (UEI): |
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Parent UEI: |
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NSF Program(s): |
Animal Developmental Mechanism, EPSCoR Co-Funding |
Primary Program Source: |
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Program Reference Code(s): |
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Program Element Code(s): |
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Award Agency Code: | 4900 |
Fund Agency Code: | 4900 |
Assistance Listing Number(s): | 47.074, 47.083 |
ABSTRACT
Neurodegenerative diseases including Alzheimer?s, Parkinson?s, ALS, and Huntington?s disease pose a serious healthcare and societal challenge with an estimated prevalence of >7 million cases in the US. These are protein misfolding diseases in which the combination of environment, stress, and aging trigger the conversion of normal proteins into non-functional and deleterious aggregates known as amyloids whose accumulation over time leads to neuronal death. One overlooked but critical challenge for treating toxic aggregates is that protein aggregation is also adaptive, serving vital biological functions such as long-term memory, storage of peptide hormones, and melanin polymerization in animals. It is now also clear that protein aggregates are widespread in normal animal development and their mis-regulation upon introducing non-native proteins capable of disentangling aggregates results in developmental defects. The objective of this proposal is to characterize the presence and role of amyloid aggregates during early development and to investigate their regulation by a novel class of chaperones which may be key to aggregate processing during animal development. Understanding the regulation of developmentally important aggregates will lead to insights into aggregate-based pathologies and novel developmental mechanistic strategies utilizing functional protein aggregates to regulate cell fate specification. The Broader Impact activities include developing new inquiry-based learning activities to increase gender and minority diversity in STEM fields and implementing an annual 6-week Ambassador in Training Program (ATP) to train a class of ~10 undergraduates in science communication so they can lead enhanced Departmental tours to visiting potential students and their families.
The PIs recently identified multiple specific amyloid bodies during the early stages of animal development supporting the hypothesis that animal aggregates are an important component of early development. The objective of this proposal is to characterize the presence and role of amyloid aggregates during early development and to investigate their regulation by the ABCF proteins which have been previously demonstrated to affect aggregation reporters and native prions in yeast, resolubilization of denatured proteins in vitro, and amyloid processing during animal development. The finding that amyloid aggregates are widespread in early development prompted a new way of thinking about and investigating amyloid aggregates in development. This proposal capitalizes on the complementary and synergistic experimental advantages of C. elegans and S. cerevisiae to test the hypothesis that ABCF proteins are novel, well-conserved and heretofore underappreciated disaggregases that regulate proteostasis in yeast and membrane-less organelle formation in animals, thereby controlling the soluble, functional proteome in a cell fate-specific manner. Aim 1 tests the role of ABCF genes in tissue and cell type specificity of aggregation during animal development. Aim 2 characterizes the role of ABCF in regulating RNA processing (P) body constituent aggregation in worms and yeast, and Aim 3 determines the mechanism of action of Abcf proteins as chaperones. Together, these aims describe a comprehensive examination of how amyloids and their dedicated disaggregases serve as novel regulators of key events in early animal development including storage, propagation, and distribution of maternal and zygotically synthesized proteins that can be released as required.
This project is jointly funded by IOS/Developmental Systems Cluster and the Established Program to Stimulate Competitive Research (EPSCoR).
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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