Projects and Grants per year
Grants and Contracts Details
Description
Abstract
Heart disease and stroke are the No. 1 and 5 causes of deaths in the US. Both Type 1 and Type 2
diabetes mellitus (T1DM and T2DM) significantly increases the risk for heart attacks and strokes.
Intense glycemic control has been reported to reduce major cardiovascular events by >30% in T1DM,
suggesting that hyperglycemia is one of the major contributors to DM-associated heart attack and
stroke risk escalation. However, how hyperglycemia exacerbate such risk is unclear. Platelets are
vascular first-responders that activate for hemostasis upon blood vessel damage; whereas
pathogenic platelet activation leads to spurious thrombosis and acute vascular obstruction. This
proposals aims to understand how hyperglycemia leads to platelet hyperactivity and their increased
propensity to form thrombi in DM, and to develop new therapeutic strategies to mitigate DM-
associated heart attacks and strokes. Utilizing an integrated metabolism toolkit including state-of-the-
art Stable Isotope Resolved Metabolomics (SIRM), we demonstrated critical role of altered platelet
metabolism in thrombin-induced platelet activation. Specifically, thrombin stimulation alters platelet
metabolism that is centered on glycogen metabolism, pentose phosphate pathway (PPP), and
fructose 1,6-bisphosphate (F1,6BP), namely, “the glycogen-PPP-F1,6BP axis”, modulating energy,
redox and calcium homeostasis in platelets and leading to their activation. Literature and our
compelling preliminary data further reveal that hyperglycemia increases glycogen storage and its
mobilization that generates ATP, PPP inhibition, reactive oxygen species (ROS), and intracellular
calcium [Ca2+]i, all of which are in line with increased propensity for platelets to activate. Therefore,
our overarching hypothesis is that hyperglycemia changes the glycogen-PPP-F1,6BP axis in platelets
to drive platelet hyperactivity and thus thrombotic risk in DM. This CCTS UK-WU DRC project will
focus on pilot studies addressing two key questions raised by the reviewers of our recent R01
application which scored 29 percentile. In Aim 1, we will determine how F1,6BP regulates [Ca2+]i
under normoglycemic and hyperglycemic conditions. In Aim 2, we will determine how hyperglycemia
alters glucose uptake, intraplatelet glucose levels, and PPP-mediated ROS regulation. Our team is in
a unique position to address our hypothesis, as we possess recognized expertise in metabolism and
metabolomics (Qingjun Wang PhD and Matthew Gentry PhD), platelet biology (Sidney Whiteheart
PhD), and T1DM (Lisa Tannock MD), and we have strong partnership with the University of Kentucky
Metabolomics and Redox Metabolism Cores. Upon completion of the proposed project, we will have
acquired additional crucial preliminary data delineating hyperglycemia-induced changes in the
glycogen-PPP-F1,6BP axis and supporting a novel mechanism for metabolic dysregulation in
platelets to mediate hyperglycemia-induced platelet hyperactivity and thrombosis in DM. Our work will
also identify new therapeutic targets for mitigating DM-associated heart attacks and strokes.
Status | Finished |
---|---|
Effective start/end date | 2/23/13 → 11/30/22 |
Funding
- Washington University in St. Louis
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Projects
- 1 Finished
-
University of Kentucky Pilot and Feasibility Research Program
Kern, P. (PI)
Washington University in St. Louis
2/23/13 → 11/30/23
Project: Research project