Eosinophilia occurs in a variety of clinical disorders including parasitic infections, hypereosinophilic syndrome, cancer, and atopic diseases. Eosinophils are derived from lineage-committed hematopoietic progenitor cells expressing the transcription factor GATA-1 and interleukin-5 receptor alpha (IL-5Ra). Although the significance of GATA-1 in eosinophil development is well established, the regulatory pathways that direct the differentiation of the eosinophil lineage-committed progenitor to mature eosinophils are not well understood, especially when compared with other hematopoietic lineages. The long term goals of the candidate, Dr. Fulkerson, are to identify novel therapeutic targets to block eosinophil production and recruitment for the treatment of patients with eosinophilic asthma and other inflammatory disorders. Dr. Fulkerson is dedicated to a career in academic medicine and to becoming an independent research investigator. The training plan outlined in this proposal will provide Dr. Fulkerson an opportunity to establish a scientific niche and facilitate the maturation of Dr. Fulkerson into an independent physician scientist with submission of a R01 grant in year three of the proposal. The objective of this proposal is to delineate the regulatory activity of the transcription factor Spi-C in eosinophil maturation. The role of Spi-C in mature eosinophils or eosinophil differentiation is completely unknown. The proposed studies are expected to provide a detailed understanding of the pathways important for eosinophil differentiation, survival and effector function via regulation of IL-5Ra expression and expression of eosinophil granule proteins. Defining the molecular regulators of eosinophil function and IL-5 responsiveness will undoubtedly provide key information with clinical applications, especially given the IL-5Ra- and IL-5-directed therapies that are currently under avid development. The central hypothesis of this proposal is that the transcription factor Spi-C coordinates with the transcription factors PU.1 and GATA-1 to regulate eosinophil differentiation via regulation of expression of genes important for eosinophil survival, proliferation and effector function. We will test this hypothesis with three specific aims. First, we will identify the role of Spi-C in eosinophil maturation using a novel in vitro culture system developed by Dr. Fulkerson that results in phenotypically mature eosinophils. Second, we will characterize the regulation of IL-5Ra by Spi-C and PU.1. Finally, we will determine the role of Spi-C and PU.1 in regulating expression of eosinophil granule proteins. Together, the proposed studies will elucidate the role of Spi-C in eosinophil differentiation. Specifically, the studies will delineate the regulation of granule protein expression and IL-5 responsiveness by Spi-C and PU.1. As release of granule proteins is an important effector function of eosinophils and IL-5 signaling is critical to eosinophilia associated with disease, further defining their regulation could lead to new therapeutic targets in eosinophil-associated disorders. Project Narrative Eosinophil accumulation and activation in tissues occurs in a variety of clinical disorders including parasitic infections, hypereosinophilic syndrome, cancer, and atopic diseases and results in the release of cytotoxic granule proteins that activate and damage neighboring cells leading to tissue damage, organ dysfunction and patient morbidity. The proposed studies are expected to provide a detailed understanding of the pathways important for eosinophil differentiation, survival and effector function, particularly production of granule proteins. This proposal will provide key information with clinical applications, especially given the eosinophil- targeted therapies that are currently under avid development.

Public Health Relevance

Eosinophil accumulation and activation in tissues occurs in a variety of clinical disorders including parasitic infections, hypereosinophilic syndrome, cancer, and atopic diseases and results in the release of cytotoxic granule proteins that activate and damage neighboring cells leading to tissue damage, organ dysfunction and patient morbidity. The proposed studies are expected to provide a detailed understanding of the pathways important for eosinophil differentiation, survival and effector function, particularly production of granule proteins. This proposal will provide key information with clinical applications, especially given the eosinophil- targeted therapies that are currently under avid development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI093673-03
Application #
8418742
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2011-02-04
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$91,932
Indirect Cost
$6,810
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Fulkerson, Patricia C; Schollaert, Kaila L; Bouffi, Carine et al. (2014) IL-5 triggers a cooperative cytokine network that promotes eosinophil precursor maturation. J Immunol 193:4043-52