Blood-brain barrier genomics, proteomics, and new transporter discovery

Abstract

Summary:The blood-brain barrier (BBB) is an impermeable cellular interface that physically separates the blood from the interstices of the brain. The endothelial cells lining the brain blood vessels form the principle barrier, and their unique phenotype is a consequence of dynamic interactions with several perivascular cell types present in the brain parenchyma. In addition, BBB dysfunction has been observed in the large majority of neurological diseases, but the causes of aberrant vascular behavior are generally unknown. Because of its barrier phenotype, drug delivery to the brain has also proven to be a very difficult task. Global genomics and proteomics analyses are currently being used to examine BBB function in healthy and diseased brain to better characterize this dynamic interface. It is becoming increasingly evident that these approaches have the potential to clarify the unique attributes of a healthy BBB, to identify therapeutic targets in diseased brain, and to identify novel conduits for noninvasive delivery of drugs against these targets. This review will discuss the application of genomics and proteomics to blood-brain barrier research and will offer views on the prospects of such approaches.

Modelling the endothelial blood-CNS barriers: a method for the production of robust in vitromodels of the rat blood-brain barrier and blood-spinal cord barrier

“…Due to this fact, in vitro primary cell models of highly differentiated endothelial cells from the BBB and BSCB remain a critical tool for investigative and pharmaceutical biology, particularly in the species typically used in pre-clinical studies. Such in vitro primary models have been utilised for genomics and proteomics studies [30,79-81], analysing endothelial transporter function [15,16,65,82,83], studying brain metastasis of cancer cells [84], and applied to translational pharmaceutical studies, investigating small molecule drug transport [77,85,86] and toxicity [67,87]. …”

Ultrastructural damage of capillaries in the neocortex in schizophrenia

“…BBB breakdown or alterations in transport systems play an important role in the pathogenesis of HIV-1 encephalitis, Alzheimer's disease, ischemia, tumours, multiple sclerosis, and Parkinson's disease (Persidsky et al 2006). Since blood capillary distribution correlates with hemodynamic-based functional imaging in cerebral cortex (Harrison et al 2002), the development of in vivo high-resolution imaging methods combined with functional MRI and vascular and BBB genomics technologies of human brain (Pardridge 2007;Shusta et al 2005) will increase our knowledge of the role of vascular abnormalities in pathophysiology of schizophrenia and other mental disorders.…”

Integrating Pharmacoproteomics into Early-Phase Clinical Development: State-of-the-Art, Challenges, and Recommendations

“…Such validation is perquisite of the utilization of such biomarkers in later-phase studies and also provides the opportunity to generate hypothesis for further biomarker development studies [75]. Samples for biomarker validation should be part of carefully planned prospective studies preferably after consultation with regulatory authorities [8].…”