Melanosomes are a specialized organelle of melanocytes that exist in order to conduct a highly specialized task, producing and storing melanin pigment. Melanin acts as a protective agent against the damaging effects of UV radiation. Thus, the presence of melanin in human skin normally contributes to a key element promoting health. Unfortunately, melanosomes are also associated with disease causing potential. Of key concern, many of the intermediates of melanin synthesis are highly reactive quinones and capable of causing significant oxidative damage. Aberrant oxidative stress associated with pigment production has specifically been implicated in several skin diseases, including cutaneous autoimmune disease and malignant melanoma. Despite this importance, the biological processes and ultrastructural components contributing to the ability of melanosomes to contain or detoxify these compounds are largely unknown. Here, we present our preliminary experiments identifying a new melanosomal protein, GPNMB, which we hypothesize participates in the ability of melanosomes to contain or detoxify the potentially cytotoxic intermediates of melanin synthesis. We will test our hypothesis using a combination of genetic epistasis experiments that take advantage of existing Gpnmb mutant mouse strains and synchrotron based imaging techniques that utilize scanning transmission X-ray microscopy. Completion of these experiments will identify a function of the GPNMB protein in melanosomes of the skin, and begin to clarify the role of this protein in health and diseases of pigmentation. Melanosomes are a specialized organelle of melanocytes that in health produce and store melanin pigment and in disease contribute to a variety of skin diseases involving melanocytes. The goal of this research is to initiate functional tests of the newly identified melanosomal protein, GPNMB, utilizing a combination of genetic and innovative imaging approaches. Completion of these studies will yield important gains concerning the melanosomal functions of GPNMB and create needed resources that will facilitate growth of this area of research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR055697-03
Application #
7769509
Study Section
Special Emphasis Panel (ZAR1-EHB-H (O1))
Program Officer
Baker, Carl
Project Start
2008-03-10
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$74,250
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Haraszti, Tamas; Trantow, Colleen M; Hedberg-Buenz, Adam et al. (2011) Spectral analysis by XANES reveals that GPNMB influences the chemical composition of intact melanosomes. Pigment Cell Melanoma Res 24:187-96
Stauss, Harald M; Rarick, Kevin R; Leick, Katie M et al. (2011) Noninvasive assessment of vascular structure and function in conscious rats based on in vivo imaging of the albino iris. Am J Physiol Regul Integr Comp Physiol 300:R1333-43
Haraszti, Tamás; Grunze, Michael; Anderson, Michael G (2010) STXMPy: a new software package for automated region of interest selection and statistical analysis of XANES data. Chem Cent J 4:11