Investigation of the biophysical and signalling aspects of platelets exposed to glycated collagen

• Grant number: 24/07470-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2025
• End date: January 31, 2029
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Renato Simões Gaspar
• Grantee: Rômulo Brênno Lopes Fróes
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 22/05750-7 - Underlying mechanisms of cardiovascular outcomes in Diabetes: the role of glycated collagen, AP.GR

Abstract

Diabetic patients have a high risk of macrovascular complications, which are the main causes of mortality in these individuals. Platelets are key players in thrombus formation and macrovascular complications in diabetic patients. From a pathophysiological point of view, platelets are activated when they encounter vascular collagen and other extracellular matrix proteins that become exposed in areas of damage. Chronic hyperglycaemia in diabetes induces the generation of advanced glycation end products (AGEs), which accumulate in arteries and can induce the glycation of long-lived proteins, such as collagen. These AGEs act through the activation of signalling cascades via the receptor for advanced glycation end products (RAGE). Although the effects of AGEs and the relevance of collagen in platelet activation are known, there are no studies on how collagen glycation can alter platelet function. Thus, the hypothesis of this work is that the interaction between platelets and glycated collagen can trigger a series of biochemical and molecular events that result in changes in the morphology, function and intracellular signalling of platelets and can increase their activation, adhesion and aggregation, thus increasing the risk of thrombotic events in patients with type 2 diabetes. The objective is to investigate the effects of glycated collagen on platelet function and explore biophysical and biochemical mechanisms. To do this, we will first explore different collagen glycation methods and analyse platelet function through platelet aggregation and adhesion assays. Once the influence of glycated collagen on platelet function has been established, our efforts will be directed to understanding which pathways are relevant to platelet activation by glycated collagen. We will use inhibitors of RAGE and other key molecules as a way to block the effects of glycated collagen. We will analyze using atomic force microscopy (AFM) whether collagen glycation leads to changes in its stiffness and whether the platelet-collagen binding strength changes. We also intend to investigate signalling pathways through phosphoproteomics, with the aim of identifying new pathways and potential pharmacological targets activated downstream of glycated collagen. Detailed understanding of these mechanisms may offer crucial clues about the pathophysiological processes underlying macrovascular disease in diabetes.