| NSF Org: |
DMR Division Of Materials Research |
| Recipient: |
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| Initial Amendment Date: | March 26, 2021 |
| Latest Amendment Date: | May 21, 2021 |
| Award Number: | 2104854 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Nitsa Rosenzweig
nirosenz@nsf.gov (703)292-7256 DMR Division Of Materials Research MPS Directorate for Mathematical and Physical Sciences |
| Start Date: | May 1, 2021 |
| End Date: | April 30, 2025 (Estimated) |
| Total Intended Award Amount: | $550,000.00 |
| Total Awarded Amount to Date: | $550,000.00 |
| Funds Obligated to Date: |
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| Recipient Sponsored Research Office: |
3720 S FLOWER ST FL 3 LOS ANGELES CA US 90033 (213)740-7762 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
825 Bloom Walk, Bldg. #148 Los Angeles CA US 90089-0102 |
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Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
CONDENSED MATTER PHYSICS, BIOMATERIALS PROGRAM |
| 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): | 47.049 |
ABSTRACT
NON-TECHNICAL SUMMARY
Perhaps the most intriguing aspect in looking to structures within the cell to inspire the next generation of novel materials is not their bulk structural properties but the cellular ability to ?reprogram? these structures. Much as reprogramming software allows it to perform different tasks, reprogramming materials allows them to take on novel functions after production. This is especially evident in select proteins that phase separate into protein-rich and protein-dilute liquid phases, much as oil added to water will separate into an oil-rich liquid phase. This phase separation has been shown to be controlled by phosphorylation, or the addition of a charged phosphate group to the protein. Not all phosphorylations are created equal; phosphorylation at certain sites within the protein will eliminate the ability to phase separate while others still can control the transport of molecules in-and-out of the protein-rich liquid phase. However, the inability to simultaneously assess the sequence of phosphorylation (or ?phosphorylation code?) and the corresponding materials properties of the protein-rich liquid phase in the cell has made it difficult to design synthetic materials that offer similar reprogramming capability.
This project seeks to overcome this obstacle by using novel biochemical engineering techniques to manufacture proteins with specific phosphorylation codes and subsequently measure the materials properties of these phase separating-proteins. In doing so, a framework will be created to design other materials with similar reprogramming capabilities and potentially generate a new class of biomimetic materials for therapeutic and consumer use. Beyond that, given the multidisciplinary scientific and engineering requirements, this project will not only provide training opportunities for the next generation of interdisciplinary scientists but seek to expand that pipeline by providing research opportunities for students at local community colleges in the greater Los Angeles area.
TECHNICAL SUMMARY
Intrinsically disordered proteins (IDPs) persist as biopolymers in solution and can undergo phase separation into protein-rich liquid droplets, akin to polymer coacervation. These subcellular structures serve unique purposes, ranging from organelle sequestration to potentially behaving as bio-reactors within the cell. However, biology has built in an additional layer of sophistication; IDPs can be ?reprogrammed? via post-translational modifications to alter the materials properties, enabling a range of dynamic properties that would be impractical with well-folded proteins.
One particular modification, phosphorylation (or the addition of a divalently-charged phosphate group), has been shown to independently control the phase behavior and biomacromolecule transport properties of synapsin, an IDP that forms synapsin-rich liquid droplets within the neuron. While control of these properties is an inviting target for biomaterials investigation, deciphering the ?phosphorylation code? of modifications that can occur at multiple, distinct sites and correlating these codes to their resultant biological function remains a challenging obstacle. To overcome this barrier, insights from polymer science and physical chemistry will be used to target specific phosphorylation codes most likely to alter materials properties. Then, cell-free protein synthesis strategies will be used to express and purify synapsin with specific phosphorylation codes and measure their resultant biomaterials properties. Ultimately, this data will form the basis of a design framework that has explanatory and predictive power for reprogramming other IDP-based biomaterials and even synthetic polymer systems.
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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