Importance of the topic
Ageing and related co-morbidities are rapidly increasing unresolved health and socio-economic problems in the EU. With a projected 45% increase in the number of people aged 65 and over in the next 20 years. There is an economic burden in financing the rising healthcare costs and access to a dignified and independent life for the aging population. Therefore, there is an urgent need to invest in the development of effective diagnostic and therapeutic tools for cost-effective maintenance of healthy ageing. Decline of brain functions represent one of the main health challenges in ageing. The functional state of the CNS is greatly dependent on the quality of the vasculature it can be said that– “You are as old as your arteries”. This concept can be redefined – you are as old as you microvessels and capillaries. This is especially true for the brain. There is increasing evidence that the cerebral microvasculature and the neurovascular unit plays a critical role in age related brain dysfunctions. In Europe the estimated number of people suffering of age related brain dysfunction is about 9.9 million and the total direct costs of medical care of these patients are of approximately 135 billion dollars. A clinical study performed in Romania between 2011-2012 [1] indicated that among the 238 males and females investigated – having an average age of 77.44±6.6 years – 25% were diagnosed with dementia. Age related vascular dysfunctions can include development of senescence associated inflammatory phenotype, BBB breakdown, blood flow decrease microhemorrhages and microinfarcts, vessel rarefaction and neurovascular uncoupling. In order to resolve the unmet medical and social need of effective prevention and/or treatment of cerebrovascular dysfunction, identification of molecular and cellular targets are particularly important and only innovative strategies could lead to the development of specific treatments. In our proposal we will address specifically mechanisms of cell based endothelial repair in age related processes.
Objectives
The proposed basic research addresses the issue of cerebral microvascular functionality in aging and aging related processes. This is an underxplored health related problem with exploding importance: neither the underlying mechanisms nor successful therapeutical approaches are known. The project is a hypothesis driven proposal with translational value which is based on solid preliminary data of the PI. The uniqueness of the proposal is a complex approach of the problem based on the followings:
- i) Investigation of the role of senolysis in the incorporation of EPCs in the brain microvascular endothelium in aging and aging related processes, ii) Combination of molecular techniques with advanced in vivo imaging, iii) High translational value due to combination of in vivo imaging and functional tests of the NVU. The project leader investigated several aspects of NVU function in vivo and in vivo so far including attachment of cancer cells to the cerebral endothelium and age associated inflammatory processes of the NVU. The present proposal combines the expertise in cell adhesion and aging studies to put the basis of a cell based therapy of age related cerebral microvascular function.
Objective 1: To determine the key aspects of endothelial precursor cell (EPC) incorporation into the capillary network of the brain.
Objective 2: To identify key elements of communication between the endothelial precursor cells with pre-existing endothelial cells and with other components of the neurovascular unit (pericytes and astrocytes).
Objective 3: To assess the benefits of endothelial renewal on the functionality of the neurovascular unit.