The Role of Mitochondrial Toxicity in Metabolic Complications of Pediatric HIV

Boston Children'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): My goal is to become an independent investigator in the field of pediatric infectious diseases, with a concentration in metabolic disease associated with pediatric and adolescent HIV infection. Under the guidance of my mentors, Dr. Christopher Duggan and Dr. Tracie Miller, I have developed a comprehensive training plan that will allow me to develop and implement an independent research study, pursue training in clinical research methodologies followed by completion of a Masters in Public Health degree, and learn laboratory techniques for conducting and interpreting assays of mitochondrial dysfunction. Most importantly, I will have the opportunity to work with a national, NIH-funded, multi-center cohort study in which I will have the primary role in the implementation of an independent substudy as well as a leading role in developing future studies in the field of HIV-associated metabolic disease and mitochondrial dysfunction. Environment: Children's Hospital Boston and Harvard School of Public Health are known for their world- renowned faculty, several of whom will serve as mentors and advisors for me and my project, an established Clinical Research Program which provides support for clinical investigators in all aspects of grant and protocol development and implementation, a General Clinical Research Center/Clinical Translational Study Unit, the NIH-funded pan-university,collaborative Harvard Catalyst Program for the establishment of a Clinical and Translational Science Center, and a wide array of educational seminars and training programs designed specifically for faculty who are conducting clinical research. Research: My research endeavor addresses a newly emerging challenge that we face in HIV care - potential adverse effects of antiretroviral therapy (ART). Metabolic complications such insulin resistance and lipid abnormalities are risk factors of premature myocardial infarction, and there is increasing evidence that the mechanism for these metabolic complications, especially insulin resistance, may be mitochondrial dysfunction. Preliminary studies in HIV-infected children indicate that 14% of these children already exhibit insulin resistance by the time they are adolescents. Studies in HIV-infected adults demonstrate that mitochondrial dysfunction occurs in conjunction with ART and that individuals with mitochondrial abnormalities are more likely to have insulin resistance. Our aims are to first characterize body composition abnormalities, nutritional issues, and metabolic complications in HIV-infected children by analyzing a large, existing database of diet, anthropometric measures, laboratory studies (lipid profiles, glucose, insulin) and DEXA scans that have been collected in HIV-infected children over a 19-year period. We will then conduct a national, multi-center study in collaboration with the Pediatric HIV/AIDS Cohort Study (PHACS) to determine whether mitochondrial dysfunction and hyperlactatemia are associated with insulin resistance or specific antiretroviral agents. For this second Aim over 400 HIV-infected children as well as controls will be enrolled, and PBMC and buccal swab assays to detect mitochondrial oxidative phosphorylation abnormalities and evidence of oxidative stress will be conducted.