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Comprehensive Proteomic Classifier for the Molecular Characterization of Pulmonary Sarcoidosis

Award Number: R01HL153613
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Comprehensive Proteomic Classifier for the Molecular Characterization of Pulmonary Sarcoidosis - PROJECT SUMMARY The primary goal of this study is to construct predictive models (classifiers) of pulmonary sarcoidosis and progressive (P) vs. non-progressive (NP) disease that will ultimately serve to improve outcomes of pulmonary sarcoidosis. We have assembled a unique investigative team with expertise in proteomics, immunology, genomics, sarcoidosis clinical care, as well as bioinformatics and statistics. Sarcoidosis is a diagnostically challenging immune-mediated systemic disease. It results in significant morbidity and mortality, primarily due to progressive pulmonary disease, although the factors that drive pulmonary disease and P vs. NP disease are unknown. The strategies to treat pulmonary sarcoidosis, including the triggers to initiate treatment, are non- specific; treatment usually relies on suppressing the immune system with corticosteroids and is associated with considerable side-effects. Transcriptional changes in the lung and blood have defined a signature of P disease in cross-sectional studies. Since proteins are the main effectors of cellular function and their alterations result in disruption of biologic systems and disease development, they are a logical source of biomarkers. Our preliminary data from bronchoalveolar lavage fluid and cells demonstrate significant proteome wide alterations in pulmonary sarcoidosis vs controls and P vs NP disease. We hypothesize that effective markers of disease and those distinguishing progressive from non-progressive disease will reflect biological processes active in disease and progression. Secondarily, by characterizing cellular proteins, global phosphorylation events and cell-specific RNA expression, we will define known proteins/gene/pathways such as the PI3K/Akt/mTOR and other serine-threonine kinase signaling mechanisms as well as novel pathogenic proteins/genes, such as endocytic and aryl hydrocarbon receptor signaling, which will have implications for mechanism and therapy. We will use high-resolution mass spectrometry (MS), advanced bioinformatics and computational tools in well- phenotyped sarcoidosis patients. In Aim 1, we will determine a disease-specific classifier for diagnosing sarcoidosis using a Discovery Cohort of sarcoidosis cases and diseased and healthy controls (already recruited) for the development and Validation Cohort (recruited for this study) of sarcoidosis cases and controls to verify and optimize the classifier performance. In Aim 2, we will identify a protein classifier of P vs NP disease using the same approach as in Aim 2. In Aim 3 we will use a novel single-cell RNA-sequencing approach, CITE-seq to identify transcription from specific cells, and integrate it with protein changes, including examination of global phosphorylation events to identify kinase signaling and discover cell-specific cellular proteins/genes associated with disease and progression in a subset of our Validation Cohort. At the end of this study, we will have defined diagnostic biomarkers of disease and progression that can be translated easily to the clinic. We will also gain insights into the sarcoidosis pulmonary proteins and transcripts that may serve as potential therapeutic targets and provide potential mechanistic information with future study.


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 = $0 )
2026	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	000	5	9/5/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $79,036 )
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	001	5	7/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$517,232
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	002	5	8/8/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Lung Diseases Research	003	4	9/3/2025	NON-COMPETING CONTINUATION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Lung Diseases Research	000	4	7/22/2025	NON-COMPETING CONTINUATION	-$438,196
														Subtotal = $79,036

Issue Date FY: 2024 ( Subtotal = $690,310 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Lung Diseases Research	000	4	8/7/2024	NON-COMPETING CONTINUATION	$690,310
														Subtotal = $690,310

Issue Date FY: 2023 ( Subtotal = $700,508 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Lung Diseases Research	000	3	8/15/2023	NON-COMPETING CONTINUATION	$700,508
														Subtotal = $700,508

Issue Date FY: 2022 ( Subtotal = $700,327 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Lung Diseases Research	000	2	7/15/2022	NON-COMPETING CONTINUATION	$700,327
														Subtotal = $700,327

Issue Date FY: 2021 ( Subtotal = $699,474 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Lung Diseases Research	000	1	8/5/2021	NEW	$699,474
														Subtotal = $699,474

Grand Total All Awards = $2,869,655

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Comprehensive Proteomic Classifier for the Molecular Characterization of Pulmonary Sarcoidosis

Award Number: R01HL153613

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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