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Mechanistic links between mutations in the CLPB gene and congenital neutropenia

Award Number: R21AI166525
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: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanistic links between mutations in the CLPB gene and congenital neutropenia - PROJECT SUMMARY/ABSTRACT Hereditary biallelic mutations in the CLPB gene are the cause of congenital neutropenia associated with MEGCANN, a rare autosomal recessive disease (OMIM entry #616271). In its severe form, the disease leads to death by a few months of age as a result of significant neurologic symptoms or life-threatening infections. Recently identified de novo monoallelic mutations in the CLPB gene act in a dominant-negative manner and also cause severe congenital neutropenia. The CLPB gene encodes a broadly expressed mitochondrial protein containing several ankyrin repeats and a single AAA+ (ATPases Associated with diverse cellular Activities) module. The molecular mechanism of CLPB function in neutrophil precursor cells is not known, and the mitochondrial defects elicited by mutated CLPB variants and their link to defective granulopoiesis are poorly defined. We hypothesize that CLPB is essential for the metabolic shift from glycolysis to mitochondrial respiration during neutrophil differentiation. We will test this hypothesis by completing two Specific Aims. In Aim 1, we will determine the role of CLPB in mitochondrial morphology, metabolism, and neutrophil differentiation using myeloblastic cell line models of granulopoiesis. This Aim will test the sub-hypothesis that CLPB plays an essential role in mitochondrial remodeling and metabolic reprogramming during neutrophil differentiation. In Aim 2, we will examine the effect of disease mutations on the interactions between CLPB and key regulators of mitochondrial dynamics and cristae morphology. This Aim will test the sub- hypothesis that the principal difference between the effects of biallelic vs. monoallelic mutations on the CLPB activity arises from distinct interaction propensities of the mutated CLPB variants. At the outcome, our studies will provide a new insight into the role of CLPB in neutrophil differentiation, will help understand the molecular defects of the disease CLPB variants, and will set the stage for developing potential treatments for neutropenias caused by CLPB mutations.


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 = $0 )
2025	2023	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	2	5/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $191,406 )
2023	2023	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	2	5/9/2023	NON-COMPETING CONTINUATION	$191,406
														Subtotal = $191,406

Issue Date FY: 2022 ( Subtotal = $242,539 )
2022	2022	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Allergy and Infectious Diseases Research	000	1	5/27/2022	NEW	$242,539
														Subtotal = $242,539

Grand Total All Awards = $433,945

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Mechanistic links between mutations in the CLPB gene and congenital neutropenia

Award Number: R21AI166525

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: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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