NSF Org:	CHE Division Of Chemistry
Recipient:	UNIVERSITY ENTERPRISES, INC.
Initial Amendment Date:	September 13, 2023
Latest Amendment Date:	September 13, 2023
Award Number:	2327946
Award Instrument:	Standard Grant
Program Manager:	John C. Jewett jjewett@nsf.gov  (703)292-5373 CHE  Division Of Chemistry MPS  Direct For Mathematical & Physical Scien
Start Date:	September 15, 2023
End Date:	August 31, 2026 (Estimated)
Total Intended Award Amount:	$420,201.00
Total Awarded Amount to Date:	$420,201.00
Funds Obligated to Date:	FY 2023 = $420,201.00
History of Investigator:	Stefan Paula (Principal Investigator) stefan.paula@csus.edu James Miranda (Co-Principal Investigator)
Recipient Sponsored Research Office:	University Enterprises, Incorporated 6000 J ST STE 3700 SACRAMENTO CA  US  95819-2605 (916)278-6402
Sponsor Congressional District:	07
Primary Place of Performance:	California State University, Sacramento 6000 J ST SACRAMENTO CA  US  95819-2605
Primary Place of Performance Congressional District:	07
Unique Entity Identifier (UEI):	N58JMBDDUGU7
Parent UEI:
NSF Program(s):	Chemistry of Life Processes
Primary Program Source:	01002324DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s):	8038, 9229
Program Element Code(s):	688300
Award Agency Code:	4900
Fund Agency Code:	4900
Assistance Listing Number(s):	47.049

ABSTRACT

With the support of the Chemistry of Life Processes Program in the Division of Chemistry, Stefan Paula of Sacramento State University is studying the development of small molecules capable of stimulating the activity of an enzyme whose natural function is the transport of calcium ions across cell membranes; namely the sarco/endoplasmic reticulum calcium ATPase (SERCA). Use of the novel small molecules to modulate the activity of the SERCA enzyme would allow the investigator to observe the effects of altered calcium concentrations inside the cell. The new molecules are designed to enhance enzyme activity and as such would complement a class of molecules known to reduce SERCA activity. The research will involve the training of students in a variety of techniques frequently employed in biomolecular chemistry research. As part of the project, molecular modeling techniques and the synthesis of specific compounds will be incorporated in three upper division courses at Sacramento State University.

Intracellular calcium levels are tightly controlled by the action of calcium transporters such as SERCA because they are critical regulators of many cellular processes. The major goal of this project is the development of small molecules that modulate the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA). Specifically, the Paula research group is aiming to establish the first tools for chemical biology that unregulate the activity of SERCA to study of the effects of increased or decreased intracellular calcium levels in living organisms. Whereas the use of SERCA inhibitors as research tools is well-established, activators have thus far received very little attention. Using a synergistic combination of computational and experimental approaches, the project seeks to close this gap by generating novel SERCA activators, establishing the molecular determinants for SERCA activation at the molecular level, and evaluating the new compounds in vivo. Organic synthesis of potential SERCA activators, activity assays with purified SERCA, molecular modeling, and cell-based assays are to be used to accomplish these research goals. The planned study appears to be the first systematic exploration of SERCA activators and is expected to provide valuable knowledge in SERCA-ligand structure-activity relationship space and potentially very valuable tools for chemical biology.

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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