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Unraveling the molecular events driven by CaMKII in Ca2+-coupled cells

Award Number: R35GM145376
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: 09/24/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Unraveling the molecular events driven by CaMKII in Ca2+-coupled cells - PROJECT SUMMARY Cell to cell communication is critical for function in all multicellular organisms. A key factor for intercellular communication is regulation by Ca2+ concentration. Ca2+/calmodulin dependent protein kinase II (CaMKII) is a Ca2+ sensitive enzyme that is encoded by four genes in mammals: α, β, γ, and δ. There is an incredible amount of diversity generated from the four vertebrate CaMKII genes. Alternative splicing produces up to 386 transcripts, which leads to the production of 386 proteins that are then differentially post-translationally modified, and mix to form hetero-oligomeric complexes, ultimately culminating in thousands of chemically distinct CaMKII proteoforms. We are specifically interested in the crucial roles CaMKII plays in long-term memory formation (neurons: α, β), fertilization (oocytes: γ), and cardiac physiology (cardiomyocytes: δ). Intriguingly, these cells all communicate using Ca2+ oscillations but on vastly different timescales (minutes to milliseconds). How does one enzyme accommodate this multifunctionality? We hypothesize that selective splicing and modification creates a unique set of CaMKII variants expressed in specific cell types, thereby leading to differential functional outputs. Fully elucidating these complex biological roles requires a deeper understanding of CaMKII variation at the sequence and protein level, structural and conformational ramifications of these variations, and how these variables affect CaMKII interactions within the cell. In this proposal, we seek to expand our understanding of CaMKII function inside cells using a combinatorial approach of sequencing, biochemistry, structural biology, and cellular assays. Completion of the proposed work will allow us to uncover the molecular basis for the many roles of CaMKII in neurons, cardiomyocytes, and oocytes – with far-reaching implications on therapeutic intervention for neurologic disease, cardiac dysfunction, and infertility.


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 = $458,488 )
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	4	8/21/2025	NON-COMPETING CONTINUATION	$398,750
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	002	4	8/22/2025	SUPPLEMENT FOR EXPANSION	$59,738
2025	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	3	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $458,488

Issue Date FY: 2024 ( Subtotal = $517,656 )
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	2	6/11/2024	SUPPLEMENT FOR EXPANSION	$29,679
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	002	3	8/26/2024	SUPPLEMENT FOR EXPANSION	$89,227
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	3	8/23/2024	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $517,656

Issue Date FY: 2023 ( Subtotal = $398,750 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	2	8/31/2023	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2022 ( Subtotal = $345,584 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	1	9/23/2022	NEW	$345,584
														Subtotal = $345,584

Grand Total All Awards = $1,720,478

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Unraveling the molecular events driven by CaMKII in Ca2+-coupled cells

Award Number: R35GM145376

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: 09/24/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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