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Spatially resolved characterization of proteoforms for functional proteomics

Award Number: UH3CA256959
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Spatially resolved characterization of proteoforms for functional proteomics - PROJECT SUMMARY/ABSTARCT Differentiated cells have distinctive patterns of epigenetic marks including various post-translational modifications (PTMs) on histones that may work in concert to control transcriptional programs. Since epigenetic marks are often altered following exposure to environmental toxins and play multiple roles in disease pathogenesis, the ability to measure histones in a tissue and cell context is a major analytical objective and challenge. Mass spectrometry (MS) based proteomics is a powerful tool for characterizing histone alterations in multiplexed and non-targeted fashion. However, conventional bottom-up (i.e. peptide-level) MS cannot provide complete characterization of the stoichiometry and combinations of multiple PTMs, and other combinatorial sources of variation, that collectively make up any single gene's set of proteoforms (i.e. functional units of a proteome). Top-down (i.e. proteoform-level) MS addresses this challenge by omitting the proteolysis and thus allowing access to the functional proteoforms. However, top-down MS suffers from low sensitivity and dynamic range due to challenges in separation and detection of large and low-abundance proteins and laborious purification steps required to achive high proteome coverage. This severely limits our ability to analyze small samples and employ top-down MS to generate proteoform-aware images of tissues required for a deeper understanding of human organ functioning in health and disease. We have recently developed nanodroplet sample preparation (nanoPOTS) for highly sensitive bottom-up proteomics and extended this approach to tissue imaging with 100 µm spatial resolution. Herein, we propose to develop and deploy nanoPOTS-based top-down MS to enable characterization of proteoforms in tissue sections with near single cell resolution. To increase the resolution from thousands of cells to near single cell, we will employ advanced MS imaging (MSI) approaches. MSI data will be cross-referenced with global proteomics data obtained via microscale top-down MS of microdissected tissue regions. The UG3 phase efforts will be focused on histones and kidney as a development platform and leverage a unique combination of microscale top-down LCMS, MSI and novel image processing and visualization tools. In the UH3 phase, we will construct comprehensive proteoform-specific maps of multiple tissue types and facilitate multimodal molecular mapping of specific functional units of the kidney by leveraging the HubMAP Consortium ongoing efforts. Successful completion of this research will allow for comprehensive characterization of the full spectrum of proteoforms in tissues and cells thus addressing an important and under- studied area of biology and critical gap in HuBMAP efforts.


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: 2026 ( Subtotal = -$3,469 )
2026	2023	BATTELLE MEMORIAL INSTITUTE	902 BATTELLE BLVD	RICHLAND	WA	99354	BENTON	USA	Trans-NIH Research Support	000	4	1/21/2026	NON-COMPETING CONTINUATION	-$3,469
														Subtotal = -$3,469

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BATTELLE MEMORIAL INSTITUTE	902 BATTELLE BLVD	RICHLAND	WA	99354	BENTON	USA	Trans-NIH Research Support	000	4	4/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $688,935 )
2023	2023	BATTELLE MEMORIAL INSTITUTE	902 BATTELLE BLVD	RICHLAND	WA	99354	BENTON	USA	Trans-NIH Research Support	003	4	9/8/2023	NON-COMPETING CONTINUATION	$600,000
2023	2022	BATTELLE MEMORIAL INSTITUTE	902 BATTELLE BLVD	RICHLAND	WA	99354	BENTON	USA	Trans-NIH Research Support	001	3	4/19/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2022	BATTELLE MEMORIAL INSTITUTE	902 BATTELLE BLVD	RICHLAND	WA	99354	BENTON	USA	Trans-NIH Research Support	000	3	3/20/2023	EXTENSION WITH OR WITHOUT FUNDS	$88,935
2023	2022	BATTELLE MEMORIAL INSTITUTE	902 BATTELLE BLVD	RICHLAND	WA	99354	BENTON	USA	Trans-NIH Research Support	002	3	7/17/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $688,935

Issue Date FY: 2022 ( Subtotal = $400,000 )
2022	2022	BATTELLE MEMORIAL INSTITUTE	900 BATTELLE BLVD	RICHLAND	WA	99352	BENTON	USA	Trans-NIH Research Support	000	3	9/6/2022	EXTENSION WITH OR WITHOUT FUNDS	$400,000
														Subtotal = $400,000

Grand Total All Awards = $1,085,466

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Spatially resolved characterization of proteoforms for functional proteomics

Award Number: UH3CA256959

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/08/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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