Award Abstract # 2126302
ISS: Quantifying the Effect of Unloading on Extracellular Matrix Remodeling in the Musculoskeletal System

NSF Org: CMMI
Division of Civil, Mechanical, and Manufacturing Innovation
Recipient: THE REGENTS OF THE UNIVERSITY OF COLORADO
Initial Amendment Date: July 26, 2021
Latest Amendment Date: June 2, 2023
Award Number: 2126302
Award Instrument: Standard Grant
Program Manager: Shivani Sharma
shisharm@nsf.gov
 (703)292-4204
CMMI
 Division of Civil, Mechanical, and Manufacturing Innovation
ENG
 Directorate for Engineering
Start Date: September 1, 2021
End Date: November 30, 2025 (Estimated)
Total Intended Award Amount: $399,997.00
Total Awarded Amount to Date: $407,997.00
Funds Obligated to Date: FY 2021 = $399,997.00
FY 2023 = $8,000.00
History of Investigator:
  • Sarah Calve (Principal Investigator)
    sarah.calve@colorado.edu
  • Virginia Ferguson (Co-Principal Investigator)
Recipient Sponsored Research Office: University of Colorado at Boulder
3100 MARINE ST
Boulder
CO  US  80309-0001
(303)492-6221
Sponsor Congressional District: 02
Primary Place of Performance: University of Colorado at Boulder
3100 Marine Street, Room 481
Boulder
CO  US  80303-1058
Primary Place of Performance
Congressional District:
02
Unique Entity Identifier (UEI): SPVKK1RC2MZ3
Parent UEI:
NSF Program(s): Special Initiatives,
BMMB-Biomech & Mechanobiology
Primary Program Source: 01002324DB NSF RESEARCH & RELATED ACTIVIT
01002122DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 028E, 070Z, 116E, 9102, 9178, 9231, 9251
Program Element Code(s): 164200, 747900
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.041

ABSTRACT

This project will study the mechanisms that lead to tissue degradation in microgravity. Exposure to spaceflight or reduced mechanical loading on Earth induces marked bone loss, muscle atrophy, and degradation of soft tissues. Despite advances in exercise and pharmacologic countermeasures designed to reduce musculoskeletal deterioration on Earth and in spaceflight, the protection is incomplete and response to these interventions are variable. Many studies have focused on the molecular and cellular mechanisms that underlie atrophy and subsequent recovery. However, little attention has been given to the extracellular matrix (ECM), the material in which cells reside. The ECM is a complex network that varies in composition between specific tissues depending on the mechanical and functional demands. Changes to the ECM can permanently alter tissue material properties, prevent resident cells from re-establishing homeostasis, and affect functionality. There is a need to better understand the fundamental changes that occur in ECM composition due to microgravity that compromise tissue functionality.

In this study, temporal changes in ECM proteins in response to, and after recovery from, microgravity will be investigated to test the following hypothesis: disuse of the musculoskeletal system irreversibly affects the ECM by reducing protein turnover and increasing enzymatic and non-enzymatic cross-links, leading to the incomplete restoration of functionality after a return to 1g. Unlike gene expression that significantly varies within minutes, a common measure to assess for the physiological effects of microgravity, the proteome changes over hours to days, and provides a more stable indicator of physiology that can withstand reentry, landing, and transport of mice from the ISS. Metabolic labeling and proteomic methods will be combined to track ECM turnover in vivo by providing mice with non-canonical amino acids (ncAAs) that are incorporated into proteins using endogenous cellular machinery. ncAAs possess bioorthogonal handles that enable the enrichment of newly synthesized proteins through click reactions with complementary chemical groups. The murine proteome will be labeled with ncAAs at different timepoints after the onset of microgravity to provide a robust ?time-stamp? of proteins formed in all tissues in the body in response to unloading. The study will first identify the optimal parameters to label newly synthesized ECM proteins on Earth and the ISS, then test response of the musculoskeletal ECM to two different unloading paradigms: hindlimb suspension on Earth and spaceflight on the International Space Station. Concomitant study of three musculoskeletal tissues: bone, tendon, and skeletal muscle, and the use of mass spectrometry, will reveal biomarkers and pathways that are important to disuse atrophy and subsequently recovery across musculoskeletal tissues. In addition, the study will provide an unprecedented resource for CASIS to disseminate ncAA-labeled tissues through established tissue-sharing mechanisms that will benefit a wide range of secondary science investigators.

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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