The current application proposes to advance the candidate's program in patient-oriented research through formal training in omics science and mentorship, through an increased level of mentoring of young investigators, and through a research project that will build on the candidate's previous work and afford opportunities to develop his omics research portolio. The research project aims to close knowledge gaps regarding the significance of key advanced glycation endproducts (AGEs) to cardiovascular and renal disease in the general population. To this end, it will undertake gold-standard measurement of a panel comprising the major plasma AGEs, and particularly the quantitatively and functionally most important adducts, methylglyoxal hydroimidazolone (MG-H1) and 3-deoxyglucosone-hydroimidazolones (3DG-H), which have scarcely been evaluated in general clinical or population settings to date.
For Aim 1, the project will leverage an ongoing study applying state-of-the-art echocardiography and magnetic resonance imaging (MRI) in women with, or at risk for HIV infection, in the Women's Interagency HIV Study (WIHS) to evaluate the relation of plasma AGEs to abnormal myocardial mechanics and fibrosis in this high-risk population.
For Aims 2 and 3, the project will parlay the availability of serial measures of glomerular filtration and standardized ascertainment of cardiovascular events among middle-aged to older adults from the Multi-Ethnic Study of Atherosclerosis (MESA) to investigate the associations of plasma AGEs with progression of chronic kidney disease and incident cardiovascular disease. These studies will provide trainees with a range of exposures to clinical and epidemiologic research to allow their development as investigators. Further, availability genetic/genomic, epigenomic, transcriptomic and metabolomic data in MESA will permit exploration of the omic correlates of AGE levels, setting the stage for larger-scale investigations in the future. Hence, the combination of formal coursework, increased mentorship, and the leveraging of existing research infrastructure to address research questions of major clinical importance will provide the candidate with increased capabilities for POR in precision medicine, and afford opportunities for the growth of his mentees as researchers in this and other disciplines.
This proposal will allow the applicant to develop new skills to identify important genes or molecules that contribute to heart disease and stroke from among very large numbers of candidates. In addition, the applicant will train to improve his mentorship abilities, and increase his commitment to mentoring trainees in patient-oriented research. As part of these goals, the applicant will conduct a research project to evaluate the role of sugar modification of proteins, and the body's inability to prevent this, as a risk factor for heart disease, stroke and kidney disease in the general population and in women at risk for, or infected with, human immunodeficiency virus.
| Huck, Daniel M; Hanna, David B; Rubin, Leah H et al. (2018) Carotid Artery Stiffness and Cognitive Decline Among Women With or at Risk for HIV Infection. J Acquir Immune Defic Syndr 78:338-347 |
| Massera, Daniele; Biggs, Mary L; Walker, Marcella D et al. (2018) Biochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study. Diabetes Care 41:1901-1908 |
