Irina Pikuleva, Ph.D.
Jules and Doris Stein RPB Professor of Ophthalmology and Pharmacology
Case Western Reserve University
Department of Ophthalmology and Visual Sciences
2085 Adelbert Road, Institute of Pathology, Rm 303
Cleveland, Ohio 44106
Phone: (216) 368-3823 Fax: (216) 368-3485
Email: irina.pikuleva@case.edu
Research Focus: Cholesterol and age-related macular degeneration

Research Summary
Dr. Irina Pikuleva delineates the link between cholesterol and age-related macular degenertaion (AMD). Her current major interest is in cytochrome P450 CYP27A1 (mediating removal of cholesterol and other sterols from many tissues including the retina, vascular endothellium and macrophages) and isolevuglanidins (oxidized products of arachidonic acid). In collaboration with Dr. R. Salomon at Case and Dr. I. Turko at the National Institute of Standards and Technology, Dr. Pikuleva and C. Charvet, a graduate student in her laboratory, have recently discovered that CYP27A1 is modified by isolevuglandins in human retina and developed a scheme shown in the figure below. This is now under investigation in Dr. Pikuleva's laboratory (see the art gallery) by studying purified recombinant CYP27A1 modified with different authentic isolevuglandins; by analyzing cadaveric human retinal samples utilizing the bleeding edge mass spectrometry methodology called multiple reaction monitoring; by evaluating CYP27A1 knockout animals using advanced diagnostic instrumentation such as ultra high resolution optical coherence tomograph and by clinical studies.

In parallel with the vision-related projects, Dr. Pikuleva continues her pharmacology-related projects including biophysical studies of P450s. In collaboration with Dr. C.D. Stout from the Scripps Research Institute, she investigates the structural basis of drug binding to P450 46A1, the key enzyme for cholesterol elimination from the brain, and recently crystallized P450 11A1, the mitochondrial enzyme controlling the first step in overall steroid hormone biosynthesis. Both P450s are expressed in the retina and may play a role in the maintenance of the retinal cholesterol homeostasis.

Putative Cascade of Events Initiated by Increased Isolevuglandin Production. The upper box shows three general contributors to oxidation of polyunsaturated fatty acids resulting in the formation of isolevuglandin-protein adducts.  The middle box shows the specific area of interest in the Pikuleva Laboratory pertinent to cholesterol homeostasis and CYP27A1, the major contributor for enzymatic cholesterol elimination in the retina, which could also be involved in elimination of toxic 7-ketocholesterol and transcriptional regulation of the retinal cholesterol homeostasis via generation of a biologicaly active 5-cholestenoic acid. The lower box shows some of the pathophysiological consequences that could be associated with increased isolevuglandin production. Overall, the proposed scheme provides a general mechanistic link between aging/oxidative stress/inflammation and age-related macular degeneration (AMD) and cardiovascular disease (CVD).

Art Gallery
Biosketch
Laboratory
Publications