Copper (Cu) is an essential trace element for normal growth and development and for the proper differentiation and function of the innate immune system. Cu deficiency causes severe neutropenia, a depletion of the phagocytic cells that represent the first line of defense in bacterial and fungal infections, thereby rendering patients susceptible to life-threatening infectious disease. Neutropenia also occurs as a consequence of radiation therapy in cancer patients, in response to drugs such as antibiotics, sedatives and anti-inflammatory agents, and as congenital or idiopathic forms of the disease. While many of the components that carry out Cu transport, distribution and utilization are well-established, the molecular mechanisms by which mammals sense Cu deficiency, and the involvement of these mechanisms in neutrophil development, represent a critical gap in our knowledge. We have discovered that a key transcriptional repressor protein in myeloid precursor cells that is required for neutrophil development, Gfi1, is severely destabilized in response to a genetic- or dietary-imposed Cu deficiency. In this proposal we outline two specific aims that will (1) identify key molecular pathways by which Cu deficiency leads to Gfi1 degradation and neutropenia and (2) test the hypothesis that dietary manipulation of Cu levels can ameliorate neutropenia. The innovative components of this proposal include: (1) establishment of a mechanistic basis for Cu deficiency- induced neutropenia (2) the elucidation of novel molecular mechanisms for Cu regulation of innate immune cell differentiation via protein degradation and (3) ascertain the potential for remediation of neutropenia by Cu supplementation. Taken together, the studies outlined in this proposal have the potential to discover novel Cu signaling pathways that modulate the development of key innate immune cells that are the first line of defense against bacterial and fungal infection.

Public Health Relevance

Copper is an essential dietary component for human health and copper deficiency causes impaired function of the immune system leading to infectious disease. The research outlined in this application is designed to identify how mammals sense and respond to copper deficiency to properly promote immune cell function and to prevent infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI106013-02
Application #
8605173
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Nasseri, M Faraz
Project Start
2013-01-15
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$211,950
Indirect Cost
$76,950
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Festa, Richard A; Helsel, Marian E; Franz, Katherine J et al. (2014) Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection. Chem Biol 21:977-87