"Our aim is to deepen the understanding of the molecular and cellular mechanisms that link brain vascular dysfunction and dementia with the hope that our results will be translated into the development of early diagnostic methods and treatments." Blanca Díaz-Castro
UK DRI Group Leader
Dr Blanca Díaz-Castro joined the UK DRI at Edinburgh in October 2019. She obtained her PhD degree at the University of Seville - Institute of Biomedicine of Seville (IBiS) and after a brief stay at Northwestern University, Chicago, she completed her postdoctoral research at University of California, Los Angeles. Her career has been centred on the study of molecular and cellular aspects of astrocyte biology that contribute to neuronal function in health and disease. In this UK DRI project, Blanca will focus on dementia research by using her expertise towards the understanding of how blood brain barrier cells communicate with each other and act as a bridge between the periphery and the brain.
1. At a glance
The role of the blood-brain-barrier in dementia
The brain is an organ of unparalleled sophistication and a fine control of its microenvironment is essential to maintain proper function. Key to this challenge is a specialised blood vessel structure called the blood-brain-barrier (BBB). Crucially the BBB controls the movement of substances between the brain and the rest of the body including restriction of dangerous toxins and pathogens.
Dysfunction of the BBB is one of the earliest events in neurodegenerative diseases that cause dementia, hence it is important for scientists to work out why this might be happening and how we can stop it. The BBB is a complex structure made up of many different types of cells and Dr Blanca Díaz-Castro believes greater understanding of them will be fundamental in deciphering what goes wrong in disease.
Over the course of this UK DRI project, Blanca and her team will investigate interactions between some of the cells found in the BBB, including astrocytes and brain endothelial cells. Astrocytes are part of the BBB whilst being in intimate contact with neurons to modulate their function and provide support. Brain endothelial cells are important structural cells lining the inside of brain blood vessels and constitute the first fence of the barrier. By studying the relationship between these cells in a healthy and disease context, Blanca hopes to identify key targets for therapeutics.
2. Scientific goals
Unlike other organs, the exchange of substances between the blood and the brain is tightly regulated by a multicellular functional entity called the Blood Brain Barrier (BBB). The BBB provides a cellular boundary that restricts the invasion of toxins and pathogens into the brain, controls the uptake of molecules from the blood, metabolizes nutrients and clears the brain of toxic by-products. Failure in BBB homeostasis leads to severe neurological disorders.
Remarkably, BBB dysfunction is one of the earliest observations in neurodegenerative diseases and precedes neurodegeneration. In spite of the crucial function of the BBB and efforts made to understand the mechanisms that underlie its dysfunction, there are important aspects of BBB physiology that remain largely unexplored. How is the BBB maintained? How do the BBB cellular components interact? What are the molecular pathways leading to BBB dysfunction?
The two most widespread components of the BBB are the brain endothelial cells (BECs) and the astrocytes. BECs form the first barrier between the blood and the brain parenchyma thanks to protein complexes called tight junctions (TJs) that keep BECs closely bound. Astrocytes have a unique strategic position in the brain by intimately contacting neurons and covering the vasculature of the brain through specialized structures called astrocyte end-feet. The understanding of the BBB cell interactions is necessary to better comprehend the BBB maintenance and pathology.
The studies undertaken in this UK DRI project, led by Dr Blanca Díaz-Castro, will enable the development of new scientific tools and disease therapies by both identifying unknown BBB dysfunction mechanisms and providing target proteins to design treatments capable of crossing the BBB.
Main objectives and research goals:
1. Comparative characterisation and functional exploration of astrocyte and BEC interactions during BBB maturation, and in neurological disease.
2. Functional mechanistic assessment, in vivo and in vitro, of new astrocyte-BEC interaction pathways unveiled by health and disease comparative studies.
3. Team members
Dr Isabel Bravo-Ferrer (Postdoctoral Researcher)
Dr Steve Hill (Postdoctoral Researcher)
Within UK DRI:
Prof Karen Duff (UK DRI at UCL)
Prof Anna Williams (Co-investigator, UK DRI at Edinburgh)
Prof Dario Alessi (Associate Member, MRC-PPU, University of Dundee)
Beyond UK DRI:
Dr Jill Fowler (University of Edinburgh)
Blood brain barrier, brain vascular disease, dementia, astrocyte, brain endothelial cells
Proteomics, RNA-seq, confocal and in vivo multiphoton imaging, behavioural assessment, blood brain barrier culture models
7. Key publications
Diaz-Castro, B.*, Bernstein, A.M., Coppola, G., Sofroniew, M.V. and Khakh, B.S.*, 2021. Molecular and functional properties of cortical astrocytes during peripherally induced neuroinflammation. Cell reports, 36(6), p.109508 (*corresponding authors)
Nagai J., Bellafard A., Zhe Q., Yu X., Ollivier M., Gangwani M.R., Diaz-Castro B., Coppola G., Schumacher Bass S M., Golshani P., Gradinaru V., Khakh B.S. AstrocyteGq GPCR signaling attenuation in vivo. Neuron 2021 Jun 10;S0896-6273(21)00376-7.
Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia. Blanca Diaz-Castro, Alexander M. Bernstein, Giovanni Coppola, Michael V. Sofroniew, Baljit S. Khakh. bioRxiv 2020.12.27.424483; doi: https://doi.org/10.1101/2020.1...
Escartin, C., Galea, E., Lakatos, A. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci (2021). https://doi.org/10.1038/s41593...
Diaz-Castro B., Gangwani M., Yu X., Coppola G. and Khakh B.S. Astrocyte molecular signatures in Huntington’s disease. Science Translational Medicine 2019 Oct 16;11(514).
Chai H.*, Diaz-Castro B.*, Shigetomi E., Monte E., Octeau J.C., Yu X., Cohn W., Rajendran P.S., Vondriska T.M., Whitelegge J.P., Coppola G. & Khakh B.S. Neural circuit-specialized astrocytes: genomic, proteomic, morphological and functional evidence. Neuron 2017 95(3):531-549.e539. *Equally contributing authors.
Jiang R., Diaz-Castro B., Looger L. L. & Khakh B. S. Dysfunctional calcium and glutamate signaling in striatal astrocytes from Huntington’s disease model mice. J Neurosci. 2016 36(12):3453-70.
Diaz-Castro B.*, Pardal R.*, Garcia-Flores P., Sobrino V., Duran R., Piruat J.I., Lopez-Barneo J. Resistance of glia-like central and peripheral neural stem cells to genetically induced mitochondrial dysfunction-differential effects on neurogenesis. EMBO Rep. 2015 16(11):1511-9. *Equally contributing authors.
Murphy-Royal C., Johnston A., Boyce A., Diaz-Castro B., Institoris A., Peringod G., Zhang O., Stout R., Spray D., Thompson R., Khakh B., Bains J., and Gordon G. Stress gates an astrocytic energy reservoir to impair synaptic plasticity. Nature Communications 2020, Apr 24;11(1):2014.
Diaz-Castro B., Pintado C.O., Garcia-Flores P., Lopez-Barneo J., Piruat J.I. Differential impairment of catecholaminergic cell maturation and survival by genetic mitochondrial complex II dysfunction. Mol Cell Biol. 2012 32(16):3347-57.