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Design Principles of Size-Control of Organelles Growing in a Shared Pool of their Building Blocks

Award Number: R35GM147556
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Design Principles of Size-Control of Organelles Growing in a Shared Pool of their Building Blocks - ABSTRACT Living cells contain a variety of distinguishable parts called organelles which have characteristic sizes and specific functions. These organelles grow in a shared pool of their respective building blocks, and are remarkably able to maintain their structure despite a rapid exchange of their building blocks. This prompts a question: how are the sizes of organelles growing in a shared pool of building blocks actively controlled by the cell? Years of biochemical experiments have revealed a plethora of proteins involved with these structures, yet, due to the high-dimensionality of the variables involved, how they all work together to create properly-sized organelles is still not well understood. Mathematical modeling and simulations, thus, provide an exciting avenue to tackle these questions, with the added benefit of identifying key tunable knobs for biochemists to run streamlined experiments. Over the last few years, using these techniques on organelles like actin cable and flagellum, I identified that a negative feedback to the size, mediated by a diminishing pool of building blocks or key accessory proteins specific to the organelle, was critical in controlling the size of a growing organelle. Significantly, the key experimental knobs that we suggested, have since been used to test the predictions of my quantitative models. My results enabled us to understand the design principles for constructing a single structure, yet how competing structures assemble and maintain their sizes while sharing a common pool of building blocks remains an open question. Over the next five years, our goal is to quantitatively analyze the mechanisms used by the cell to share building blocks between competing structures. Proteins involved in disassembly of organelles offer a solution - in addition to disassembling pre-existing structures, they can provide key length-sensing feedback to the size of individual structures sharing a common pool of building blocks. Using simulation schemes and theoretical tools that I pioneered, we will identify discernible signatures of specific disassembly mechanisms, and quantitatively describe their repercussion on the sharing of common resources between different competing structures. Using actin structures and nucleolus as our model systems, we will design theory-driven experiments to verify our predictions with already established collaborations, and use experimentally tunable knobs to discriminate between different mechanisms that cells use to share building blocks between competing structures. A quantitative understanding of molecular mechanisms affecting organelle growth will accelerate the development of new therapies to combat many human neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (abnormalities in actin assembly) and Parkinson’s and Alzheimer’s disease (nucleolus abnormalities).


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 = $355,144 )
2025	2025	ROCHESTER INSTITUTE OF TECHNOLOGY	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	4	7/25/2025	NON-COMPETING CONTINUATION	$355,144
														Subtotal = $355,144

Issue Date FY: 2024 ( Subtotal = $355,144 )
2024	2024	ROCHESTER INSTITUTE OF TECHNOLOGY	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	3	7/18/2024	NON-COMPETING CONTINUATION	$355,144
														Subtotal = $355,144

Issue Date FY: 2023 ( Subtotal = $355,144 )
2023	2023	ROCHESTER INSTITUTE OF TECHNOLOGY	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	2	7/24/2023	NON-COMPETING CONTINUATION	$355,144
														Subtotal = $355,144

Issue Date FY: 2022 ( Subtotal = $355,144 )
2022	2022	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	1	8/3/2022	NEW	$355,144
														Subtotal = $355,144

Grand Total All Awards = $1,420,576

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Design Principles of Size-Control of Organelles Growing in a Shared Pool of their Building Blocks

Award Number: R35GM147556

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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