Deanery of Biomedical Sciences:
Astrocytes are morphologically very complex cells that tile the entire brain. Unlike any other cell in the brain, astrocytes enwrap the brain vascular tree through subcellular structures called astrocyte endfeet, while their cell body and thousands of branches live in the brain parenchyma and interact with other cells (PMID: 31283899). Thus, astrocytes have the potential of receiving signals from the vasculature to influence neural cells and vice versa (PMID: 33058289). These unique features make astrocytes ideal targets for treatments against neurological diseases. While most of the research on astrocyte biology has been focussed on astrocyte-neuron interactions, very little is known about how astrocytes interact with the brain vasculature. This is important because brain vasculature dysfunction increases with ageing and leads to cognitive decline (PMID: 34699267). In this context, the white matter is particularly interesting, as a high proportion of vascular lesions are observed in this brain area with age and in vascular genetic diseases. Despite its relevance, very little is known about how astrocytes interact with the white matter vasculature in health or disease.
Here, we propose to use imaging and proteomics tools, rodent models and human tissue to determine the effects of age and cerebral small vessel disease (cSVD) on astrocyte-vasculature interactions with the goal of identifying molecular mechanisms that may mediate white matter dysfunction.
Aims:
Aim 1: Characterize astrocyte-vasculature interactions in young rodents and humans. Little is known about the morphological and molecular relationship of astrocytes with the brain white matter vasculature and how conserved it is across species. To investigate their morphological arrangements, we will use optical and electron microscopy in young rodents and human brains. Proteomics experiments will be performed to define signalling pathways that may mediate these interactions in both species. These experiments will determine shared characteristics of astrocyte-vasculature interactions between humans and rodents, extensively used animal models to investigate human disease.
Aim 2: Identify white matter astrocyte-vasculature alterations with age and in cSVD. Focussing on the conserved mechanisms between rodents and humans identified in aim 1, and using similar techniques, we will assess what aspects of astrocyte-vasculature interactions are affected with age and in cSVD.
With this experiments, we will contribute to the understanding of astrocyte-vasculature interactions in the white matter in health and their alteration in disease. Our results will provide a foundation to, in the future, investigate molecular pathwaysthat could potentially be targeted to prevent white matter dysfunction in neurological disease.
Training:
Our project offers a unique opportunity for a PhD student to be supervised by clinical and non-clinical researchers that will allow the student to become an expert on astrocyte-vasculature interactions, and state of the art techniques like high resolution imaging and proteomics of rodent and human brains.
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