Platelets play an essential role in the complex process of thrombus formation. Disruption of mitochondrial membrane and its membrane potential, can lead to inefficient ATP production, excessive ROS production, oxidation of protein, and fatty acids, and subsequent apoptosis. Interestingly, platelets do not have a nucleus to mediate many of the major components of apoptosis (e.g. DNA damage and fragmentation) and response to apoptosis. We and others have recently demonstrated platelet apoptosis in diabetes mellitus (DM) leading to increased thrombosis. There is an urgent need identify new mechanisms, and develop new therapies, to target platelet apoptosis and thrombosis, for the growing population of diabetic patients. We now present new preliminary results demonstrating mitochondrial dysfunction and apoptosis in diabetic platelets. Moreover activation of a novel mitophagy process appears to protect the platelet from apoptosis. Additionally, prostacyclin and epoxyeicosaenoic acid (arachidonic acid metabolites) may also protect diabetic platelets from apoptosis and thrombosis. Based on our Preliminary Results we hypothesize that mitochondrial dysfunction in platelets, arising from hyperglycemia, leads to platelet apoptosis and increased thrombosis. Through three Specific Aims we will decipher the mechanism by which hyperglycemia induces platelet mitochondrial dysfunction and assess pathways distal to platelet mitochondrial dysfunction leading to apoptosis (Specific Aim #1). We will additionally study the process of mitophagy, and how this impacts platelet mitochondrial function and apoptosis (Specific Aim #2).
Specific Aim #3 will determine whether epoxyeicosaenoic acid and prostacyclin, two potentially novel therapeutic approaches, can protect against mitochondrial dysfunction and apoptosis in diabetes mellitus. Our team of internationally recognized experts in the areas of platelet biology, mitochondrial biology and apoptosis will in the short term decipher important new mechanisms regulating mitochondrial dysfunction and apoptosis in diabetes mellitus. In the long term we will have identified new targets for novel therapy against platelet mediated thrombosis.

Public Health Relevance

Diabetes mellitus is a growing concern in the USA with growing morbidity and mortality, and few new therapies. We have discovered that there is major platelet mitochondrial dysfunction in diabetes mellitus leading to platelet dysfunction and premature platelet death (apoptosis). Our goals are to decipher why this occurs, and how it happens, in addition to whether we can inhibit this pathological mitochondrial/apoptosis process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122815-01A1
Application #
8817070
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Warren, Ronald Q
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$416,250
Indirect Cost
$166,250
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
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