ИСТИНА

Проект направлен на изучение молекулярных шаперонов семейства HSP70 и ко-шаперонов в качестве биомаркеров для ранней диагностики лимфомы.

Heat shock proteins 70 kDa (HSP70) are multi-functional molecular chaperones which support cancer cell during whole process of its development, starting from the suppression of apoptosis, and ending up with the acquisition of a mesenchymal phenotype. The uncovered roles of HSP70 in suppressing cell death have led to the discovery of new class of inhibitors called HSP70 inhibitors. Along this line, immunological HSP70 effects served as a basis for the development of HSP70-based immunotherapy approaches based on the ability of HSP70 to activate immune cells. In line with that, HSP70-based vaccines have been assessed in I-II phases of cancer clinical trials. Our work is aimed at studying the role of HSP70 in intercellular communications in lymphomas. Lymphoma is somewhat a unique type of cancer being a malignancy of an immune system. Lymphomas are a heterogeneous group of diseases originating from certain types of lymphocytes. Therefore, the identification of predictive diagnostic biomarkers will allow for the detection of cancer in its initial stages and will serve as the basis for more effective cure for the treatment of cancer. Cancer cells communicate via extracellular vesicles (EV) which they secrete in extracellular microenvironment leading to the development of angiogenesis, migration and metastasis. In our work, we will use EV proteomic analysis and micro-RNAs profiling to analyze the expression of HSP70 chaperones and co-chaperones in liquid biopsies of patients with Hodgkin’s and non-Hodgkin’s lymphoma. Furthermore, we will analyze the expression of HSP70 chaperones and co-chaperones in EV secreted by certain types of immune cells. Based on our results, we will create a mathematical model that will allow us to identify type and stage of lymphoma by analyzing the expression of HSP70 chaperones and co-chaperones in EV isolated from fluid biopsies. To the best of our knowledge, no similar research studies have been performed elsewhere. This will be the first study to explore HSP70 family and co-chaperones in EV isolated from liquid biopsies as potential biomarkers for lymphoma diagnosis. Exosomal miRNAs that target HSP70 family members and co-chaperones were also not studied yet in patients with lymphoma. The HSP70 profile of chaperones and co-chaperones in vesicles secreted by certain types of immune cells has also not been evaluated in lymphoma patients. The results of our studies will help to identify a prognostic marker for early diagnosis of lymphoma based on heat shock proteins and co-chaperones, as well as expand our understanding of the role of HSP70 family members in cancer, which can also serve as the basis for the development of more effective immunotherapy approaches.

В нашей работе мы планируем использовать протеомный анализ, а также экспрессию микро-РНК в опухолево-специфичных внеклеточных везикулах, для анализа экспрессии HSP70 шаперонов и ко-шаперонов в жидкостных биопсиях пациентов с лимфомой Ходжкина и неходжкинской лимфомой. В дополнение к этому, будет проведен анализ экспрессии HSP70 шаперонов и ко-шаперонов во внеклеточных везикулах, секретируемых отдельными типами иммунных клеток. На основе наших результатов, мы планируем построить математическую модель, которая позволит стратифицировать пациентов по типу лимфомы и стадиям заболевания на основе экспрессии HSP70 шаперонов и ко-шаперонов в везикулах, выделенных из жидкостных биопсий пациентов с лимфомой.

После получения всех количественных данных, будет построена модель на основе алгоритмов машинного обучения для сравнения экспрессии членов семейства HSP70 и ко-шаперонов в моче и плазме крови пациентов с лимфомой Ходжкина и неходжкинской лимфомой, а также для сравнения экспрессии шаперонов и ко-шаперонов на разных стадиях и в разных типах лимфомы. После идентификации чувствительных биомаркеров, мы предпримем попытку создать простой метод ранней диагностики лимфомы на основе иммуноферментного анализа, используя антитела к выявленным белкам теплового шока и ко-шаперонам.