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A Closed Loop Control System with Live Cells in the Loop

Award Number: R21EB028489
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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A Closed Loop Control System with Live Cells in the Loop - A CLOSED LOOP CONTROL SYSTEM WITH LIVE CELLS IN THE LOOP This work proposes to develop and apply, for the ﬁrst time, control theory-derived strategies to regulate autophagy in live cells using an innovative experimental testbed with sensing and actuating capabilities. Combinations of pharmacological interventions are used extensively for the treatment of many diseases. Therefore, there is signiﬁcant potential for control theory- based treatments to enhance the well-being of patients through careful tuning of dosage delivery of multiple pharmacological reagents (PRs). Intracellular measurements of the formation of autophagy vesicles (AVs) in response to the application of various PRs will be conducted using traditional ﬂuorescence microscopy and an Amnis ImageStream Mark II Imaging Flow Cytometer, available at the University of New Mexico (UNM) Autophagy, Inﬂammation, and Metabolism in Disease Center of Biomedical Research Excellence (AIM Center), the only autophagy-focused CoBRE in the nation and in which PI Sorrentino is an Associate Member. This state-of-the-art instrument uses ﬂow cytometry and multispectral imaging to detect intracellular AVs, providing an accurate count of total AVs (the output) within individual cells. A perfusive ﬂuidic delivery system to deliver drugs (the inputs) in time and in a controlled manner will be developed as part of the proposed eﬀort. This experimental testbed will provide a proof-of-concept realization of closed-loop control of autophagy in live-cell experiments. In addition, an integrated mathematical model will be developed to describe the regulation of autophagy in live cells by considering the eﬀects of several PRs on the formation of AVs. Our control decisions will be explicated at two levels: ﬁrst, the choice of PRs to use in a combination study out of a set of available PRs; and second, the dosage function for each PR in the combination, i.e., the rate at which the PR is supplied as a function of time, with time being a continuous function. An innovative multi-scenario optimal controller will also be developed and tested to optimize the control actions in the presence of limited experimental information and uncertainty about the state of the system. The UNM AIM Center hosts a team of specialists who conduct groundbreaking research into the role of autophagy in inﬂammatory diseases and infection, and who provide mentoring opportunities for junior faculty. As an Associate Member of the AIM Center, PI Sorrentino is in a unique position within a specialized, local environment to meet with success. The long-term impact of the proposed research will be signiﬁcant, as it has considerable potential to advance scientiﬁc knowledge at the nexus of engineering and life sciences, and lead to the development of optimized therapies that could positively aﬀect the well-being of millions of patients worldwide. 1


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$19,605 )
2025	2022	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	2/6/2025	NON-COMPETING CONTINUATION	-$19,605
														Subtotal = -$19,605

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF NEW MEXICO	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	2/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $17,917 )
2023	2022	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	11/3/2022	NON-COMPETING CONTINUATION	$17,917
														Subtotal = $17,917

Issue Date FY: 2022 ( Subtotal = $161,252 )
2022	2022	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	12/27/2021	NON-COMPETING CONTINUATION	$161,252
														Subtotal = $161,252

Issue Date FY: 2021 ( Subtotal = $217,492 )
2021	2021	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	3/20/2021	NON-COMPETING CONTINUATION	$217,492
2021	2021	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	2	5/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $217,492

Issue Date FY: 2020 ( Subtotal = $180,040 )
2020	2020	UNIVERSITY OF NEW MEXICO	1700 LOMAS BLVD NE	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	3/25/2020	NEW	$180,040
														Subtotal = $180,040

Grand Total All Awards = $557,096

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A Closed Loop Control System with Live Cells in the Loop

Award Number: R21EB028489

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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