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Novel therapeutics in the prevention and treatment of cerebrovascular diseases

Name of the project

Novel therapeutics in the prevention and treatment of cerebrovascular diseases

Key idea (slogan) of the project

Focused delivery of novel therapeutics for brain protection

Partner organization

Harvard University;

Queen Mary University of London;

Technische Universitat Munchen;

University of Pennsylvania;

Peter the Great St. Petersburg Polytechnic University;

National Research Tomsk Polytechnic University.

Global scientific/technological goal (challenge) of the project

As the world’s population ages the significance of events that reduce brain function becomes a greater societal and social burden. Diseases such as stroke and neurodegeneration represent a significant problem due to the difficulty of delivering agents to the neurovasculature.

Academic supervisor of the project

Rustem Litvinov (H-index – 21)

Description of the project

The main goal of this project is to provide a solution to the problem of delivering bioactive substances specifically to sites of brain injury. New therapeutic agents and modalities will be developed and tested initially on an animal model of ischemic stroke. These methodological approaches will have the potential to be useful in a broad range of pathologies of the central nervous system, such as traumatic brain injury and Alzheimer’s disease. The study will be conducted by a multi-disciplinary group of researchers; whose combined expertise is required for the development of novel therapeutics for neurovascular diseases. Our initial studies will utilize mouse ischemic stroke models by applying unique delivery methods of standard and genetically justified therapeutics into the injury zone. There are 5 basic aims of the project: 1) the functional characterization of in vivo models of neuronal and vessel damage; 2) the biochemical and structural evaluation of the damaged tissues; 3) the synthesis of microparticles for targeted drug delivery to the neurons and vessels; 4) the development of thrombolytic and genetic modulators of the cerebral blood flow and brain function; 5) the assessment of inflammatory processes in the brain using gene expression techniques.
The main experimental system will be the middle cerebral artery occlusion model of ischemic stroke. This model will be used to assess both behavioural and electro physiological function. Samples of the cerebral vessels and brain tissue will be used for detailed biochemical and structural analysis which will evaluate the objective severity of brain damage. Consequences of stroke for cellular signaling will be studied using cell and molecular biology techniques and transgenic mice. The data from complex examination of cerebral vessels and brain tissues will be analyzed with the use of state-of-the-art bioinformatics methodology which will be used to build an integrative model of ischemic stroke.
A key part of the project is the development of a new approach for targeted drug delivery to the sites of brain infarction. This will enhance the treatment efficacy of cerebral thrombosis using with known thrombolytics. At the next stage of research, new delivery options and potential drugs will be studied, such as microcircular DNAs, cytokines, modulators of nitric oxide activity, and etc., that would improve cerebral blood flow and reduce the inflammation at sites of brain damage.
The strength of the project is the interdisciplinary and highly qualified team with the potential to reach the ambitious goals of this research. The resources of three major Russian scientific centers and four established international labs will be involved. This multifaceted international and multi-disciplinary collaboration will lead to the successful completion of this project.

Approaches to the implementation of the project

The project consists of various complementary parts.
The first part of the study is aimed at studying the pathogenesis of cerebrovascular diseases. This direction relies on the use of state-of-the-art animal models of brain injury and unique monitoring techniques, including 3D brain imaging, biochemical, electrophysiological, and electron microscopic examination of the damaged brain tissues. Changes in immune cell phenotype and the resident cells of the affected brain tissues will be analyzed using flow cytometry, cell isolation, and RNA sequencing. The control data from our previous publications (such as infarct volumes, cerebral blood flow values, characteristics of the neurological deficit, and vascular relaxation data) will be used in the proposed project. Bioinformatics analysis of these data, in particular the transcriptomic data and molecular interactome networks related to neurovascular diseases will be vital in revealing novel therapeutic avenues
The second part of the project is development of new methods and technologies for new drug synthesis and targeted delivery. We will focus on nano- and micro-carriers that deliver bioactive compounds and drugs specifically to the damaged cells and tissues. In particular, we plan to develop a unique approach based on using live blood cells as natural transporters of encapsulated materials to deliver them to certain biological targets.
The third part implies the use of known and newly developed therapeutics and a novel approach of their targeted delivery for the experimental treatment of brain damage. Thus, the goal of this proposal is development of novel approach to prophylaxis and the treatment of brain damage.

University’s experience, research and technological preliminary preparatory work

Kazan Federal University created a unique full cycle scientific and technological infrastructure in the field of Biomedicine – from research and development to practical application.
1. University Clinic – a multidisciplinary medical institution with 840 beds, providing high-tech medical care. Importantly, it has a state-accredited department for conducting clinical trials of new methods of diagnostics, treatment and rehabilitation. The clinic has a fully functional laboratory for clinical genomics, powerful sequencers and the laboratory of clinical gene diagnostics that allows to conduct analysis using nucleic acids from clinical samples.
2. Interdisciplinary centre for proteomics and genomics research. The centre is equipped with modern equipment to conduct proteomics, genomics and transcriptomics studies – capillary sequencers and next-generation sequencers, mass spectrometers with liquid and gas chromatography systems (MALDI, Electrospray, QTOF). Within the framework of the Federal target program “Research and development in priority directions of development of scientific-technological complex of Russia for 2014-2020” KFU carries out two major projects: “Development of proteogenomics based on interdisciplinary core facilities for cell studies, genomic and post-genomic research in the Volga region” and “Development of diagnostics panels for assessment of the qualitative and quantitative compositions of the microbiota from the intestinal contents”.
3. Research and education centre for pharmaceuticals was established within the framework of the Federal program Pharma-2020. The main task is the discovery and development of novel therapeutics: synthesis of pharmaceutical substances, screening for a biological activity, elucidation of the mechanism of action, preclinical studies, manufacturing of finished dosage forms.
4. The competitiveness program of Kazan Federal University builds on the successful work of OpenLab research laboratories and four centers of excellence, namely “Genomics, proteomics and biotechnology”, “Regenerative and translational medicine”, “Neuroscience” (supported by Megagrant from the Russian Government), “Pharmaceuticals”.
5. The research facilities in Kazan Federal University are well equipped for work with cell cultures and animals (in vivarium). Over the last several years the research teams mastered the modern methods of cell programming – this includes work with induced pluripotent stem cells and isolation of stem cancer cells from primary tumors.

Achieving of global leadership (excellence), as one of the project results

This project will allow the Russian Federation to achieve global leadership in two key areas of biology and translational medicine: first in the use of targeted delivery mechanisms to the brain; and second in the assessment and discovery of brain injury mechanisms at the genomic, biochemical, cellular and neuronal systemic levels.

Significance, relevance and academic novelty of the project

One of the main characteristics of this project is its multidisciplinary nature, incorporating any leading scientists from both across Russia and the rest of the world. This complex interplay between investigators of varied background means that the project will contribute to the scientific world at a number of levels including biomedicine, chemistry, pharmaceutics, cell biology, and the physics of imaging. There are a wide range of neurological disorders including neurodegeneration and brain injury, for which the ability to treat is limited by targeted delivery of therapeutic agents. This project attacks this problem head on and will directly approach the challenge of delivery therapeutics to the injured brain. Successful solution of this project will provide a significant contribution to biomedicine. Though we will initially use known thrombolytics in the initial phase, we will design novel agents that will provide a significant contribution to the chemistry of thrombosis and the function of reactive chemical species in the regulation of blood flow. We will build on known techniques of microparticle synthesis to design transport agents that can specifically target an individual tissue, in our case the neurovasculature. These studies will make a significant contribution to the science of pharmaceutics. At the most fundamental level, our studies will examine the complex signaling interplay between the tissue and the inflammatory system. We will be using state of the art techniques to understand these systems and the bioinformatics involved. This aspect of our work has the possibility to produce fundamental change in our understanding of cell signaling. Finally, we will use cutting edge technologies to visualize the changes that occur both within the vasculature and the brain. This work will push forward the bounds of the physics of imaging technology.
The principle method of dissemination: we will use for our research is through publication. It is our intention to publish in higher impact journals, but also to support these submissions by presentation at international meetings and through invited talks. Many of the investigators in this proposal give invited lectures around the world and these can provide another avenue for information dissemination. A further method of making our work visible will be to reduce our technologies to practice and thus actually alter therapeutic approaches worldwide.
The novelty of this project is based upon the application of state of the art techniques and knowledge into areas that they have not been previously applied.

Relevance and significance of the project in technologies

The project explores a novel approach for drug delivery to injured sites. Novelty is based to use natural blood cells of organism as transporter of encapsulated drugs using biological cell navigation (such as leucocytes recruitment in injured or inflammation site. Preliminary experiments confirmed uptake of microcapsules with bioactive cargo. The major technological challenge in development of drug delivery is compatibility of delivery systems. Here we propose a revolutionary approach of use own cells with new encapsulation technology which is capable to encapsulate a variety of different drugs and bioactive compounds.