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Ancillary studies to define dysregulated immune and fibrotic pathways in a well-characterized morphea cohort

Award Number: R01AR078560
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Morphea is a disfiguring autoimmune disease of the skin and underlying tissue. An unbalanced inflammatory response leads to fibrosis and atrophy of the deeper tissue, causing physical and psychological disability. Available therapies for morphea are not always efficacious and are often associated with substantial side effects. One of the biggest barriers to the development of new treatments is a lack of studies examining the pathophysiology of morphea, the initial step that leads toward the development of more directed and efficacious therapies. The Morphea in Adults and Children (MAC) and National Registry for Childhood Onset Scleroderma (NRCOS) registries, led by the principal investigators (Jacobe and Torok, respectively), have already begun to address this problem. Working together, we have investigated the protein expression and bulk transcriptional profile associated with morphea in both children and adults using protein assay, cytometry, and microarray/RNA sequencing. These data indicate that fibrosis in morphea is driven by inflammation through a network of IFN-¿ mediated genes. Despite this progress, the pathogenesis of morphea, including the exact cell populations’ producing this IFN-¿ over expression, needs to be examined in depth before new treatments can be tested. That is the goal of this proposal. Our studies will leverage both the unique resources of the MAC and NRCOS registries (the largest in the world), which are supported by a Parent Observational Cohort study grant (NIAMS R01), and the multidisciplinary and complementary expertise of the investigators (including facilities at UTSW Medical Center and the University of Pittsburgh) to conduct detailed transcriptional and mechanistic studies to fully investigate transcriptional profiles of likely pathogenic cell types and study the immunological effects of key molecules in fibroblast cultures and co-culture systems. The objectives of the proposed studies are to: 1) further define dysregulated immune pathways in morphea via transcriptomic analyses, 2) determine the association of these gene signatures to validated clinical measures and disease course to evaluate their role as biomarkers in morphea, 3) identifying inflammatory cell subsets that express these IFN-¿ mediated genes, which are likely the pathogenic cell subtypes, 4) determine fibroblast subsets and their interaction with pathogenic inflammatory cells, 5) and define the pathogenic pathways that enable the disease, by first utilizing human fibroblast cultures. The conduct of these studies will not only probe morphea to find the underlying disease mechanism, but will also produce promising targets for development of biomarkers and new therapies.


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: 2024 ( Subtotal = $275,041 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/8/2024	NON-COMPETING CONTINUATION	$275,041
														Subtotal = $275,041

Issue Date FY: 2023 ( Subtotal = $324,840 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	2/22/2023	NON-COMPETING CONTINUATION	$32,483
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/11/2023	NON-COMPETING CONTINUATION	$292,357
														Subtotal = $324,840

Issue Date FY: 2022 ( Subtotal = $358,735 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/11/2022	NON-COMPETING CONTINUATION	$32,612
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/24/2022	NON-COMPETING CONTINUATION	$326,123
														Subtotal = $358,735

Issue Date FY: 2021 ( Subtotal = $376,842 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/26/2021	NEW	$376,842
														Subtotal = $376,842

Grand Total All Awards = $1,335,458

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Ancillary studies to define dysregulated immune and fibrotic pathways in a well-characterized morphea cohort

Award Number: R01AR078560

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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