Education:
1991-1995, Ph.D.
Relative contributions of extracellular Ca2+ entry and intracellular Ca2+ release to stimulus-secretion coupling in rat pancreatic acinar and rat adrenal chromaffin cells; Graduate University for Advanced Studies, Department of Physiology, Yokohama, Japan.
1984-1989, B.S./M.S.
Effect of dexamethasone administration during stress non-responsive period in rats on pituitary-adrenocortical axis of adult animals, Departments of Physiology and Endocrinology, Novosibirsk State University, Novosibirsk Russia.
Clinical/Research Interests:
The main goal of research conducted in Busik lab is understanding the pathogenesis of diabetic complications with the focus on diabetic retinopathy. Diabetic retinopathy is one of the most disabling diabetic complications and a leading cause of blindness in adults. Despite the progress made in the last decade in understanding of the molecular mechanisms and the treatment options for the disease, diabetic retinopathy is still neither fully preventable nor curable. Although the role of hyperglycemia in the development of diabetic retinopathy has been studied in detail, the role of dyslipidemia received much less attention. Our laboratory critically contributed to understanding of the role of dyslipidemia in several areas:
1) The role of sphingolipid metabolism in diabetic retinopathy pathogenesis;
We have demonstrated that the central enzyme of sphingolipid metabolism, Acid Sphingomyelinase (ASM), is highly upregulated in diabetic retina and plays a critical role in the developments of retinal vascular pathology. ASM activation leads to increased C16 ceramide production and ceramide rich platform (CRP) formation on the surface of endothelial cells. Inhibition of CRP formation using anti-ceramide antibody is currently investigated as potential therapeutic strategy for diabetic retinopathy.
2) The effect of diabetes on the key enzyme(s) in retinal fatty acids remodeling;
Retina has very high expression level of fatty acid elongases, especially Elovl2 and Elovl4. Diabetes induced a significant decrease in retinal expression levels of Elovl 2, Elovl4 and Elovl6. Diabetes-induced downregulation of retinal elongases translated into a significant decrease in both omega 3 polyunsaturated and saturated very long chain fatty acids. Very long chain saturated fatty acids incorporate into very long chain ceramides that are further modified into 3-omega hydroxy ceramides. We have demonstrated that very long chain 3-omega hydroxy ceramides are important for normal tight junction formation and function in retinal endothelial cells and decrease in elongases in diabetes leads to blood retinal barrier breakdown.
3) Effect of diabetes on retinal cholesterol metabolism;
We have demonstrated that LXRα and LXRβ are downregulated in the retina of diabetic animal models and human retinal cells isolated from diabetic donors. Importantly, LXR activation reversed diabetes-induced retinal vascular damage, and DMHCA treatment reversed downregulation of reverse cholesterol transport genes, as well as inflammation in retinal endothelial cells. Increased levels of cholesterol in diabetic retina led to cholesterol crystal formation. Cholesterol crystals are pro-inflammatory and pro-atherogenic. Cholesterol crystal-induced damage can recapitulate all pathogenic features of diabetic retinopathy. Removal of cholesterol crystals using alpha-cyclodextrin normalized retinal permeability and function in diabetes.
4) Role of dyslipidemia in inadequate vascular repair by bone marrow derived myeloid angiogenic cells (MACs) in diabetes.
The diabetic metabolic insult leading to retinal vascular degeneration involves the initial endothelial cell damage due to low-grade chronic inflammation; that is then inadequately repaired due to compromised availability and functionality of bone marrow derived MACs. We have demonstrated that a molecular metabolic link connecting both the initial inflammation in the retina and the dysfunctional MACs involves activation ASM in both MACs and retinal vasculature.
Funding:
https://reporter.nih.gov/search/Fx3dpafO6UOIIVO4dhxjpg/projects
Select Honors & Accomplishments:
1985 Gold Medal for an excellent study, Novosibirsk (Russia) High School N81.
1985 Novosibirsk State University Scholarship.
1986-1991 Novosibirsk State University Honorary Scholarship for Academic Achievements.
1991 The First Prize for Research Presentation at XXIX All-Union Students' Conference, Novosibirsk, Russia.
1992-1995 Monbusho (Ministry of Education, Science and Culture, Japan) Scholarship.
1996 Travel Allowance to attend Frontiers in Pancreatic Physiology Meeting, Lincolnshire, IL, November 8-10, 1996.
1997 Travel Allowance to attend European Pancreatic Club meeting, London, UK, July 9-12,
1997 Research award from the Associate Dean for Research and Graduate Programs and the Office of Medical Education Research and Development, College of Human Medicine, Michigan State University.
2011 College of Osteopathic Medicine, Michigan State University Early Promise in Research Award
2017 NatSci Junior Faculty Mentoring Award, College of Natural Science, Michigan State University
2017 Research Excellence Award, College of Osteopathic Medicine, Michigan State University
2019 Distinguished Faculty Service Award, College of Osteopathic Medicine, Michigan State University
2021 Silver ARVO Fellow
Select Publications:
List of Publications at the National Library of Medicine