Award Abstract # 2324378
Animal Disaggregases and Amyloid Contributions to Early Development

NSF Org: IOS
Division Of Integrative Organismal Systems
Recipient: THE UNIVERSITY OF IOWA
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: FY 2023 = $775,000.00
History of Investigator:
  • Bryan Phillips (Principal Investigator)
    bryan-phillips@uiowa.edu
  • Jan Fassler (Co-Principal Investigator)
Recipient Sponsored Research Office: University of Iowa
105 JESSUP HALL
IOWA CITY
IA  US  52242-1316
(319)335-2123
Sponsor Congressional District: 01
Primary Place of Performance: University of Iowa
105 JESSUP HALL
IOWA CITY
IA  US  52242-1316
Primary Place of Performance
Congressional District:
01
Unique Entity Identifier (UEI): Z1H9VJS8NG16
Parent UEI:
NSF Program(s): Animal Developmental Mechanism,
EPSCoR Co-Funding
Primary Program Source: 01002324DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 9150, 9177, 9178, 9179
Program Element Code(s): 111900, 915000
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.

Please report errors in award information by writing to: awardsearch@nsf.gov.

Print this page

Back to Top of page