Determination of transcytosis proteins in cerebral capillaries by computational and experimental methods to carry drugs to the brain
Even today, 16% of daily deaths worldwide are caused by neurological diseases. One of the main reasons why these diseases are a leading cause of disability and negatively impact the daily lives of approximately 276 million people is the blood-brain barrier (BBB), which prevents more than 98% of pharmaceutical agents from entering the brain. The blood-brain barrier regulates the entry and exit of substances to create a homeostatic environment for proper brain function. Although it protects the brain from toxins and pathogens, it also restricts drug access to the central nervous system (CNS), preventing treatment of brain disorders. For this reason, there is a need for intermediate protein delivery systems in the treatment of brain diseases that can transport drugs to the brain by overcoming the BBB using non-invasive methods. This can only be achieved with transcytosis proteins expressed in the endothelial cells of the brain that form the blood-brain barrier. This requires finding transcytosis proteins that are specific to human brain endothelial cells. In this project, transcytosis proteins will be found that are expressed at high levels in brain endothelial cells and differently from endothelial cells in other organs utilizing two different unique approaches. In the first approach, transcriptomic and proteomic data from the literature obtained from human tissues and cells will be used to determine genes and proteins that are expressed differently in brain endothelial cells than in endothelial cells of other organs, and algorithms will be developed to prioritize proteins according to their location in the cell, organ perfusion rate, and pharmacodynamic response. In the second approach, two-dimensional sequence analysis and three-dimensional conformational analysis of proteins already known in the literature to be experimentally capable of transcytosis will be used to determine the motifs and features that may be responsible for this transcytosis activity. In this way, new proteins with similar properties that have the ability to transcytose can be identified. In this unique study, performed for the first time considering the protein profiles of human cells, the expression levels and transcytosis activities of proteins derived from human brain endothelial cells are experimentally controlled in human in vitro models developed using stem cell technology and closely resembling the physiology of the BBB in vivo. In addition, it will be shown that unique nano-carrier systems can be developed to deliver drugs targeting the proteins selected in this project to the brain. The results of this study will open new horizons for the development of new methods for the treatment of brain diseases and technologies for drug delivery to the brain.
