Projects / Programmes
Phase transitions in systems of nucleotide repeat expansions associated with neurodegenerative diseases
| Code |
Science |
Field |
Subfield |
| 1.02.00 |
Natural sciences and mathematics |
Physics |
|
| Code |
Science |
Field |
| B002 |
Biomedical sciences |
Biophysics |
| Code |
Science |
Field |
| 1.03 |
Natural Sciences |
Physical sciences |
neurodegenerative diseases, DNA/RNA repeat expansions, RNA granules, phase separation, liquid crystalline phases
Researchers (12)
Organisations (3)
Abstract
Recent molecular biology studies reveal that a large number of intracellular assemblies of amino acids, proteins, RNA, DNA and other intracellular compounds is driven by phase separation mechanisms, however, the physics nature of associated thermodynamic phases and phase transitions is at present still very poorly understood. Phase separation phenomena are believed to be responsible also for many disease-related modifications in the intracellular medium, among them also those connected with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). More than 30 incurable neurodegenerative diseases are at present known to be the result of genetic mutations characterised by expansions of short nucleotide repeats. Their common pathological development takes place via a phase transition of the primary RNA transcripts from a usual liquid state into a state exhibiting several congested clusters known as aberrant nuclear foci or RNA granules, whose formation has a negative impact on cellular functions. The foci interact with RNA-binding proteins, which results in inhibition of natural functions of those proteins and consequently leads to fatal errors in RNA processing and translation.
The proposed interdisciplinary project will focus on combined experimental and theoretical investigations aimed at development of fundamental understanding of different thermodynamic phases and phase transitions taking place in the above mentioned systems. The emphasis will be on pathological pathways that are presumably connected with the noncanonical folding (G-quadruplex formation) of the involved DNA/RNA strands. All investigations will be performed in-vitro and will take place with two different types of samples: (i) relatively short repetitive nucleotide sequences that are characteristic for healthy cells, and (ii) analogous long repetitive sequences that are involved in pathological processes. For both types of samples we will resolve a phase diagram of their thermodynamic phases and determine their fundamental physical properties. We expect that chromonic liquid crystalline phases will occur. We will also examine a possibility to tune the critical concentration of different phases by some selected additives or external simuli. This knowledge is crucial for development of therapeutic methods and/or pharmaceutical substances aimed at medical treatment of repeat expansions related diseases via disrupting the problematic RNA phase separation.
Significance for science
Opening new directions in the field liquid crystal research: The research on liquid crystals was for long time boosted by their technological importance for the LC display industry. A wide diversity of LC materials and operation principles for LCD devices was developed. Since the associated technologies reached their matured state, LC science is searching for new challenges, new materials, new applications and new relevance. Chromonic liquid crystals (CLC) are recently gaining attention in the LC society, because their increased complexity results in several new interesting phases and features. G-quadruplex forming oligonucleotides represent a new family in the pool of CLC materials, which is at present just in the beginning of their exploration period. The proposed project will therefore make an important pioneering step in promoting this new area of the LC research.
Increasing importance of liquid crystals in biological systems: Liquid crystals (LCs) are recently gaining increased interest in the field of biological systems and processes, as liquid crystallinity is supposed to be strongly associated with molecular crowding conditions that are normally present in intracellular medium. A connection between liquid crystallinity and genetically-based cellular malfunctions associated with formation of RNA granules is at the moment still speculative. Our project will consequently open-up a new research topic associated with importance of LC phases in genetically-based diseases.
Implanting physics principles into molecular biology: During the last decades an enormous amount of data was collected on cellular structure and functions on molecular level. In the associated efforts, the biologist usually point out individuality and complexity of the investigated systems. The involvement of physicists into the investigated problems can largely benefit from the physicists’ tendency to classify various phenomena into a small set of distinctive groups. Other important contributions that physics can bring to molecular biology are their inclination to quantification of phenomena and development of theoretical models.
Fostering policy of problem-based interdisciplinary research teams: In traditional organization of university education and scientific research various disciplines are quite separated from each other. Consequently, the research teams usually define their research problems on the basis of their educational background. However, with increasing complexity of problems and systems investigated, this principle is shifting from discipline-based towards problem-based strategies in which experts with diverse expertize collect together to examine a specific problem. The proposed interdisciplinary project that will involve researchers from physics, molecular biology, structural chemistry and material science will proof the efficiency of problem-based research teams.
Significance for the country
Opening new directions in the field liquid crystal research: The research on liquid crystals was for long time boosted by their technological importance for the LC display industry. A wide diversity of LC materials and operation principles for LCD devices was developed. Since the associated technologies reached their matured state, LC science is searching for new challenges, new materials, new applications and new relevance. Chromonic liquid crystals (CLC) are recently gaining attention in the LC society, because their increased complexity results in several new interesting phases and features. G-quadruplex forming oligonucleotides represent a new family in the pool of CLC materials, which is at present just in the beginning of their exploration period. The proposed project will therefore make an important pioneering step in promoting this new area of the LC research.
Increasing importance of liquid crystals in biological systems: Liquid crystals (LCs) are recently gaining increased interest in the field of biological systems and processes, as liquid crystallinity is supposed to be strongly associated with molecular crowding conditions that are normally present in intracellular medium. A connection between liquid crystallinity and genetically-based cellular malfunctions associated with formation of RNA granules is at the moment still speculative. Our project will consequently open-up a new research topic associated with importance of LC phases in genetically-based diseases.
Implanting physics principles into molecular biology: During the last decades an enormous amount of data was collected on cellular structure and functions on molecular level. In the associated efforts, the biologist usually point out individuality and complexity of the investigated systems. The involvement of physicists into the investigated problems can largely benefit from the physicists’ tendency to classify various phenomena into a small set of distinctive groups. Other important contributions that physics can bring to molecular biology are their inclination to quantification of phenomena and development of theoretical models.
Fostering policy of problem-based interdisciplinary research teams: In traditional organization of university education and scientific research various disciplines are quite separated from each other. Consequently, the research teams usually define their research problems on the basis of their educational background. However, with increasing complexity of problems and systems investigated, this principle is shifting from discipline-based towards problem-based strategies in which experts with diverse expertize collect together to examine a specific problem. The proposed interdisciplinary project that will involve researchers from physics, molecular biology, structural chemistry and material science will proof the efficiency of problem-based research teams.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
