H2020Индивидуална стипендия2022–2023

STEPV · Spatio-temporal Stochastic Models for Phenotype and Gene Regulation by the Human Papillomavirus

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2022-02-07 → 2023-08-06
Финансиране от ЕС: 159 700 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Вирусът HPV-16 и неговият протеин E6 променят начина, по който клетките се делят и развиват в тъканите. Разбирането на тези процеси помага при търсенето на нови антивирусни терапии за хора, които вече са заразени.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Spatio-temporal Stochastic Models for Phenotype and Gene Regulation by the Human Papillomavirus

In this project systems biology was used to develop temporal and spatiotemporal models to understand how high risk Human Papillomaviruses (HPV-16,) affect cell fate choices through 16E6 viral protein in order to affect tissue homeostasis, hence the balance between cell proliferation and differentiation. This is an important problem for society because even though vaccines exist against HPVs, they are prophilactic vaccines and therefore the development of antiviral therapies is of pivotal importance. Understanding how HPVs affect cell fate choices in a phenomenological way under tissue biology approaches as well as a mechanistic perspective under a pathway understanding is of pivotal importance in order to properly understand viral perstistence and reservior. This will help to better understand under a rigorous approach the key regulators that has to be targeted and how to optimally target them in order to develop novel antiviral effective therapies. The objectives were to understand the important question about how HPV affects tissue homeostasis through E6 both phenomenologically through the development of a cell state model describing cell states (proliferative, differentiation) in the infected epithelium. The objectives were also related to study how E6 could affect Notch pathway in order to mechanistically understand, through a pathway understanding, how cell fate choices in terms of cell proliferation and differentiation are controlled as well as explore antiviral therapies hypothesis through model simulations. In conclusion, STEPV project reached its major goals, and it was possible to validate with biological experiments a stochastic mathematical model explaining the competitve advantage of HPV over wild type (healthy) cells in terms of cell fate choices (i.e., symmetric/asymmetric division, commitment to differentiation). The model was expanded into a 2D stochastic lattice grid model capable to reproduce in space and time the HPV competitve advantage in terms of the balance between cell proliferation and differentiation at a tissue level. The model was specialized with Notch/DLL1 pathway in order to understand how HPV E6 is altering such a pathway to make stronger hypothesis about HPV competitive advantage. The model was also used as a simulator to test different biological hypothesis also regarding antiviral therapies.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Human papillomaviruses (HPVs) cause a range of serious diseases, with particular regard to cervical cancer, most anal cancers and half of head and neck cancers, and the need for new and effective antiviral therapies is of paramount importance. Important advancements regarding the HPV infection, throughout the infected epithelium, have been recently made. However, a full mechanistic understanding of how stochastic and dynamical properties of the HPV gene network interact with the cellular circuitry that controls proliferation/differentiation and cell-to-cell communication affects responses at the single cell and tissue level during infection is lacking. A better understanding of these aspects is critical to understand viral persistence, cancer progression, and to develop novel strategies for antiviral therapies. Mathematical models, developed under rigorous mathematical and biological assumptions, can be of great help in generating optimal solutions to these problems. STEPV project aims at improving the current available frameworks for stochastic tissue-level mathematical modeling, by tackling their limitations and specialize them in the context of HPVs, as well as to improve clinical/biological discoveries about HPVs infection. The specific goals are: (1) development of novel spatio-temporal modeling frameworks in order to describe HPVs gene expression and its connection with the phenotype control; (2) use of the developed models to understand the phenotype regulation by oncoproteins, understand viral persistence and propose novel antiviral strategies. By achieving these goals, STEPV will provide, for the first time, innovative modeling frameworks in the field of the computational systems biology applied to the context of HPVs infection, allowing quantitative and noninvasive tools to deeply investigate still elusive mechanisms, regarding HPVs infection, as well as investigate inaccessible or poorly understood clinical/biological scenarios.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство