Diabetes currently afflicts approximately 25.8 million people in the United States (US) and 220 million people worldwide. Type 2 diabetes mellitus (T2DM) accounts for ~95% of all diagnosed cases in the US, among which cardiovascular disease is the leading cause of mortality. Vascular dysfunction, leading to increased risk of coronary artery disease and peripheral vascular disease, remains an important clinical problem in diabetic patients. Hyperglycemia is a major causative factor of T2DM contributing to vascular dysfunction, however, there is a large gap of mechanistic studies in this area. This proposal evaluates the underlying hyperglycemia- induced alterations in the endothelium glycoproteome that lead to changes in important homeostatic signaling pathways, such as the AT1R and HTR2A signaling pathways, and result in vascular dysfunction.
The aims of this proposal utilize innovative glycoproteome and phosphoproteome enrichment, sensitive mass spectrometry technology, and physiologically relevant functional tests to explore hyperglycemia-induced protein glycosylation at the cell surface (Aim 1), alterations of the synergistic balance of intracellular O-GlcNAcylation and phosphorylation (Aim 2), and subsequent alterations in important homeostatic signaling pathways leading to vascular dysfunction (Aim 3). In order to do this, the applicant requires protected time for supervised career development in bioinformatics, proteomics as applied to physiological systems, vascular biology, clinically relevant human cohort experimentation, and professional development under the direction of Dr. Andrew Greene (Professor of Physiology-MCW) and co-mentor Dr. Michael Widlansky (Associate Professor of Medicine and Pharmacology-MCW). This research proposal and career development modules will assist in fostering the Principal Investigator in his independence such that he can lead a research program aimed at examining causal factors in T2DM. The mentored career development award will further the candidate's training in bioinformatics processing for signal pathway ontology analyses, along with continued training in proteomics analysis applied to complex systems. The applicant will also receive extensive training in vascular biology as it relates to functional studies of T2DM rat models and vessels from T2DM patients. The training agenda includes lab-based training (MCW), clinical training (MCW/Froedtert & CTSI), specialty training in external labs, coursework, and professional development seminars/workshops. This multi-disciplinary training will ensure the ability of the applicant to design, perform, troubleshot, and interpret experiments independently. Outcomes of research proposal described here will provide direct evidence to confirm or refute the fundamental hypothesis that hyperglycemia-induced glycosylation is driving specific alterations leading to vascular dysfunction in T2DM and in combination with the professional career development will foster a smooth transition of the candidate to an independently funded investigator.
The significance of this proposal is that it will employ an innovative approach to understand the causative mechanisms underlying hyperglycemia-induced vascular dysfunction during type 2 diabetes mellitus, while developing novel targets for therapeutic intervention. Outcomes of the proposed research have significant potential to make a major contribution for new treatments for improving vascular function during type 2 diabetes mellitus.
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