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MDS-Associated Spliceosome Mutations Regulate Host Defense

Award Number: R01AI155749
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/11/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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MDS-Associated Spliceosome Mutations Regulate Host Defense - ABSTRACT Myelodysplastic Syndrome (MDS) is a hematopoietic stem cell disorder characterized by myeloid cell differentiation defects and dysplastic blood cell production. The majority of MDS patients die of disease related causes, with infection or infectious complications being the most common cause. While it is known that myeloid cells exhibit functional defects in MDS patients, the extent and cause of these defects remain unclear and the corresponding effects on host defense have received limited study. With the advent of next-generation sequencing technology, analysis of somatically-acquired mutations in patient samples has become a normal part of clinical practice in MDS patients. Interestingly, the most common class of mutations found in MDS patients are mutations in various components of the spliceosome. We have determined that these MDS- associated spliceosome gene mutations lead to alterations in innate immune signaling pathways and compromise the function of myeloid cells in mouse models of spliceosome-mutated MDS. This leads to a significant defect in host defense. Based on these preliminary studies, we have hypothesized that MDS patients with spliceosome mutations are at an increased risk of infection because of immune dysfunction in their myeloid cells. To test this hypothesis, we will investigate the effects of spliceosome mutations on host defense using: (1) ex vivo studies with mouse and human neutrophils, (2) ex vivo studies with mouse and human macrophages, and (3) in vivo studies in mice expressing mutant spliceosome genes and in an analysis of clinical data from patients with MDS. These studies will determine the mechanisms underlying host defense defects in MDS patients with spliceosome mutations and will provide important clinical data about patient risk stratification.


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 = $523,165 )
2025	2025	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	5	2/28/2025	NON-COMPETING CONTINUATION	$523,165
														Subtotal = $523,165

Issue Date FY: 2024 ( Subtotal = $539,346 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	4	2/20/2024	NON-COMPETING CONTINUATION	$485,411
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	001	4	5/31/2024	NON-COMPETING CONTINUATION	$53,935
														Subtotal = $539,346

Issue Date FY: 2023 ( Subtotal = $539,346 )
2023	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	3	2/14/2023	NON-COMPETING CONTINUATION	$539,346
														Subtotal = $539,346

Issue Date FY: 2022 ( Subtotal = $539,346 )
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	2	2/1/2022	NON-COMPETING CONTINUATION	$539,346
														Subtotal = $539,346

Issue Date FY: 2021 ( Subtotal = $555,346 )
2021	2021	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	1	3/11/2021	NEW	$555,346
														Subtotal = $555,346

Grand Total All Awards = $2,696,549

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MDS-Associated Spliceosome Mutations Regulate Host Defense

Award Number: R01AI155749

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/11/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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