Studies of cholesterol maintenance in the retina and brain to delineate the importance of cholesterol-related pathways for retinal and brain functions and whether pharmacologic modulation of these pathways could lead to disease-modifying treatments for retinal and brain disorders.
Primary appointment - Ophthalmology
Secondary appointment - Pharmacology
Cholesterol is essential for life in mammals. However, if chronically in excess, it becomes a risk factor for cardiovascular and Alzheimer’s diseases and possibly several retinal diseases such as age-related macular degeneration and diabetic retinopathy. The two major areas of research in Dr. Pikuleva’s laboratory are studies of cholesterol maintenance in the retina and brain. The ultimate goal of these studies is to delineate the importance of cholesterol-related pathways for retinal and brain functions and whether pharmacologic modulation of these pathways could lead to disease-modifying treatments for retinal and brain disorders.
Currently, the eye-related projects include: 1) evaluation of hamsters as a model for studies of retinal cholesterol homeostasis; 2) pharmacologic treatments of different genetically modified mice; and 3) elucidation of retinal significance of the apolipoprotein J. In vivo retinal assessments by SD-OCT, SLO, and ERG as well as ex vivo and in vitro evaluations by histo- and immunohistochemistry, transmission electron microscopy, mass spectrometry, and other methods are used. In addition, animals are treated with deuterated water and deuterated cholesterol to quantify retinal pathways of cholesterol input.
The brain-related projects include different types of studies of cytochrome P450 46A1 (CYP46A1), the most important enzyme for cholesterol elimination from the brain. The laboratory is mapping general mechanisms, by which CYP46A1 activity modulation exerts multiple brain effects and is investigating the next generation of CYP46A1 activators. 5XFAD mice, a model of Alzheimer’s disease, are evaluated by different omics approaches and subsequent follow up experiments as well as by the quantifications of the brain amyloid load and sterol content, behavioral assessments, isotopic labeling and tracing; and other specific methodologies. In addition, crystallization of CYP46A1 in complex with different small molecules is also undertaken.
View Irina Pikuleva’s publications https://pubmed.ncbi.nlm.nih.gov/?term=pikuleva%20i