# Mechanisms of Impaired Granulopoiesis Due to CLPB Mutations

> **NIH NIH K99** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $120,911

## Abstract

Project Summary/Abstract
 The goal of the proposed research is to elucidate the molecular pathogenesis of severe congenital
neutropenia (SCN) due to mutations of caseinolytic peptidase B (CLPB). SCN is an inborn disorder of
granulopoiesis characterized by severe chronic neutropenia from birth, premature death secondary to
infectious complications, and transformation to myeloid malignancy. Through exome sequencing of a large
SCN cohort, the candidate has recently identified heterozygous missense mutations in CLPB as a new and
frequent cause of SCN. CLPB is a nuclear-encoded protein that resides within the inner mitochondrial
membrane space where it functions as a molecular chaperone to disaggregate and facilitate re-folding of
misfolded proteins. However, the mechanisms linking impaired CLPB function to a defect in granulocyte
formation are unclear. In this proposal, the principle investigator will test the hypothesis that mutant CLPB acts
in a dominant fashion to disrupt the chaperone function of CLPB, resulting in impaired mitochondrial stress
responses and induction of apoptosis in promyelocytes. To test this hypothesis, the following specific aims are
proposed: Aim 1) to determine whether CLPB mutations impair the mitochondrial response to endoplasmic
reticulum stress in granulocytic precursors; Aim 2) to examine the impact of CLPB mutations on the switch
from glycolysis to oxidative phosphorylation in early granulocytic precursors.
 The proposed studies should provide an understanding of the molecular pathophysiology of CLPB-
mutant SCN. Ultimately, a better understanding of normal and SCN-related granulopoiesis may suggest new
therapeutic approaches to treat or prevent neutropenia in patients with SCN, and in patients receiving
myeloablative chemotherapy.
 The long-term goal of this physician-scientist candidate is to establish a productive and independent
laboratory at a major academic institution studying normal and malignant hematopoiesis. The primary mentor
is Dr. Daniel Link, a distinguished scientist who is also an experienced and committed mentor. A panel of
senior investigators with complementary scientific and translational expertise will serve on a formal K99
mentorship committee to provide both scientific and career guidance. Washington University is an exceptional
environment to train junior investigators, especially those interested in hematopoiesis. There is ready access
to numerous core facilities and a strong intellectual environment with experts in stem cell biology, neutrophil
biology, mitochondrial biology, and cellular models of hematopoiesis. In addition to taking courses in
biostatistics and bioinformatics, the candidate will take advantage of the broad portfolio of workshops offered at
Washington University to help junior investigators establish and run an independent laboratory. Washington
University has committed to providing laboratory space and resources to facilitate the candidate’s transition to
independence.

## Key facts

- **NIH application ID:** 10700271
- **Project number:** 7K99HL156057-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** JULIA Therese WARREN
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $120,911
- **Award type:** 7
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700271

## Citation

> US National Institutes of Health, RePORTER application 10700271, Mechanisms of Impaired Granulopoiesis Due to CLPB Mutations (7K99HL156057-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10700271. Licensed CC0.

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