Nelinearna mehanika bioloških tkiv in njihovih tumorjev
Oznaka in naziv projekta
J1-3009 Nelinearna mehanika bioloških tkiv in njihovih tumorjev
J1-3009 Nonlinear mechanics of biological tissues and their tumors
Logotipi ARRS in drugih sofinancerjev
Projektna skupina
Vodja projekta: dr. Matej Krajnc (SICRIS) (Spletna stran)
Sodelujoče raziskovalne organizacije: Povezava na SICRIS
Sestava projektne skupine: Povezava na SICRIS
Vsebinski opis projekta
Funkcija in oblika bioloških tkiv sta tesno povezana, kar je še posebej očitno pri rakavih obolenjih, saj je prav ostopanje tkiva od njegove normalne strukture eden glavnih indikatorjev raka. Žal pa je razumevanje povezave med funkcijo in obliko tkiv zaradi kompleksnosti teh materialov velik izziv, ki zahteva znanja iz različnih vej naravoslovja vključno z biologijo, eksperimentalno biofiziko in teoretično biofiziko. V okviru predlaganega projekta se bomo tega izziva lotili z razvojem in študijo naprednih računalniških modelov bioloških tkiv, s katerimi bomo poizkušali razumeti njihove viskoelastične lastnosti, razvoj kompleksnih oblik in mehanskih sprožilcev nastanka anomalnih struktur, ki so lahko znak rakavih obolenj. Naslovili bomo tri vsebinsko povezane teme: (i) Nelinearna elastičnost epitelijskih gubanj, (ii) Rast tumorjev in (iii) Struktura in reologija trirazsežnih celičnih skupkov. V prvem delo nas bo zanimal nastanek nagubanih epitelijskih vzorcev pri epitelijskih tkivih na površinah organov. S kombinacijo diskretnega ogliščnega modela prečnega preseka epitelija in efektivne nelinearne teorije elastičnosti bomo poizkušali razumeti pogoje, ki vodijo do gubanja, ter nabor možnih oblik, ki pr item nastanejo. Še posebej nas bodo zanimali nelinearni efekti, ki vzpostavijo karakteristično valovno dolžino periodičnih vzorcev. Študija odvisnosti teh vzorcev od mehanskih lastnosti posameznih celic kot tudi mehanskih lastnosti podpornih struktur, npr. bazalne membrane in substrata, bo pomembno za razumevanje razlik med biološkimi tkivi in “običajnimi” neživimi materiali. V drugem delu bomo naslovili mehaniko rasti tumorjev tako v enoslojnih kot večslojnih epitelijih. Razvili bomo diskretni ogliščni model epitelijskih tkiv, ki bo vključeval skupek mutiranih celic s hitro rastjo in pogostimi delitvami. Posebej se bomo osredotočili na to, kako mehanske lastnosti bazalne membrane in globljih plasti tkiv vplivajo na rast tumorja in posledične deformacije tkiva kot celote. Naši rezultati bodo pripomogli k boljšemu razumevanju vloge mehanike pri nastanku in rasti tumorjev, kar bi lahko bilo pomembno pri izboljševanju metod za postavitev prognoze in metod zdravljenja. Nazadnje bomo v sklopu tretjega dela študirali strukturo in reologijo trirazsežnih celičnih skupkov. S kombinacijo preprostega statistično-mehanskega prostopa, ki temelji na Markovski verigi, in bolj detajlnega numeričnega pristopa, ki temelji na ogliščnem modelu tridimenzionalnih tkiv, bomo pozikušali razumeti kako hitre celične delitve določajo strukturo trirazsežnih rakavih celičnih skupkov, pod katerimi pogoji se skupki obnašajo kot trdnine in pod katerimi pogoji kot tekočine, ter kako različni aktivni procesi na nivoju celic vplivajo na njihove reološke lastnosti. Naši rezultati bodo predstavljali tudi pomemben korak naprej v smislu metodologije, saj zaradi kompleksnosti strukture teh materialov trenutno numerične metode za opis mehanike trirazsežnih celičnih skupkov tako na nivoju celic kot tkiv še ne obstajajo. Naše metode bodo zapolnile del te vrzeli. V sklopu predlaganega projekta bomo prišli do zanimivih rezultatov, ki bodo predstavljali pomemben prispevek na področju mehanike tkiv. Še pomembneje, skupaj z našimi novi pristopi bodo ti rezultati odprli nove smernice za nadaljne raziskave in ponudili izboljšane numerične meetode za študijo nelinearne mehanike bioloških tkiv in njihovih tumorjev.
Project description
The function and shape of biological tissues are tightly related. Indeed, one of the main indicators of disease, e.g., cancer is a disruption of normal tissue architecture. Understanding this relation is extremely challenging due to the complexity of the material and thus requires combined efforts from biologists, experimental biophysicists, and theoretical biophysicists. The proposed project aims towards developing and studying advanced computational models of biological tissues to understand their viscoelastic properties, the formation of complex shapes, and mechanical triggers of disruptions from the normal tissue architecture, common for disease, e.g. cancer. In particular the project will address three related topics: (i) Nonlinear elasticity of epithelial wrinkling, (ii) Tumor growth, and (iii) Structure and rheology of three-dimensional cell aggregates. In part (I), we will be interested in the formation of wrinkled patterns in tissues at the surfaces of organs. In particular, we will use a combination of a discrete vertex model of epithelial cross section and an effective nonlinear elasticity theory to understand the conditions for wrinkling and the variety of possible shapes. We will particularly focus on understanding the nonlinear effects that establish the characteristic wavelength of these periodic patterns. Studying how these patterns depend on the mechanical properties of individual cells as well as on the mechanical properties of supporting structures, e.g., the basement membrane and the substrate, will be important for understanding in what way biological tissues differ from “usual” nonliving materials. In part (ii), we will address the mechanics of tumor growth both in epithelial monolayers as well as in multilayered epithelia. In particular, we will develop a discrete vertex model of epithelial tissues with a rapidly growing mass of mutated cells. We will particularly focus on how the mechanical properties of the basement membrane and stroma, which support the cancerous epithelium, affect tumor growth and the subsequent tissues-scale deformations. Our results will improve the understanding of the role of mechanics in the formation and growth of tumors, which is may be important for improving methods of prognosis and treatment. Finally, in part (iii), we will study the structure and rheology of three-dimensional cell aggregates. In particular, by combining a relatively simple statistical-mechanical approach, based on the Markov chain, and more detailed cell-based computational approaches, we will try to understand how rapid cell division in tumor spheroids determines the structure of the cell packing, under what conditions these cell masses behave like solids and under what conditions like fluids, and how different cell-scale active processes affect their rheological properties. Our results will also represent an important step forward in terms of the methodology. Indeed, due to technical complexity of the structure of these active materials, no computational tools exist that could be used to address the mechanics of three-dimensional cell aggregates at the interface between the scale of individual cells and the whole-tissue scale. Our tools will certainly fill part of this void. Overall, the proposed project is expected to yield interesting results that will represent an important contribution to the field. More importantly, our novel approaches are going to open new avenues for the future research and offer improved computational methods for studying nonlinear mechanics of biological tissues and their tumors.
Osnovni podatki sofinanciranja so dostopni na spletni strani SICRIS.
Faze projekta
1. Faza: Nelinearna elastičnost epitelijskih gubanj
2. Faza: Rast tumorjev
3. Faza: Struktura in reologija trirazsežnih celičnih skupkov
Bibliografske reference
KRAJNC, Matej, STERN, Tomer, and ZANKOC, Clement. Active instability and nonlinear dynamics of cell-cell junctions. Physical Review Letters. 2021, vol. 127, no. 19, str. 198103. ISSN 0031-9007. DOI: https://doi.org/10.1103/PhysRevLett.127.198103. [COBISS.SI-ID 84201731]