Design and development of biocompatible nano- and mesosystems based on amyloid fibre formation (Q3958249): Difference between revisions
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Amyloid aggregation is of outstanding biomedical, bio- and structural-chemical importance and has attracted continued interest over the past decades (B.S. Blumberg and D.C. Gajdusek for Kuru’s disease (1976) and S.B. Prusiner for prion heritage understanding (1997) received the Nobel Medical Prize). Scientific breakthroughs in this area can only be achieved if there is a high degree of synergy between researchers, critical numbers and resources. The necessary synthetic, biochemical, spectroscopic, modelling, bioanalytical and nanotechnology capacity is now available at ELTE TTK. Our focus is the development of protein test systems, the rational design, in vitro/vivo production and development of biocompatible nanosystems. In order to achieve our research goals, we intend to establish a centre of excellence, which can bring significant breakthroughs in the field due to the development of cooperation across the whole field of molecular biochemistry, combining six different approaches and six different perspectives. Understanding the spatial structure and dynamics of proteins is a research task that is of biomedical, social and economic importance beyond chemical curiosity and importance. Proteins can be identified in almost all parts of living organisms and function effectively, in accordance with their environment, as complex systems, with well-regulated protein-protein interactions in the background, and with oligo and polymerisation processes (Tory, Perczel, Nature Genetics 2014). However, these processes sometimes lead to aggregation and amyloid dead ends. The change in conformation, which has been diagnosed by Alois Alzheimer for more than 100 years but has not yet been accurately understood on a molecular level, is only one of the amyloid aggregations experienced in the process of ‘protein ageing’. Aggregation is a thermodynamically beneficiary (Perczel 2007), and its detailed understanding and use are central elements of our application. In addition to abnormal protein aggregation, a number of non-pathogenic aggregations are also known. Functional amyloids have played an important role in evolution in bacteria (Pseudomonas), cloak proteins (Plasmodium), spider silk, biofilms, adhesion proteins, etc.; they are distinguished by their stability, flexibility, tensile strength. Our application builds on the novel and goal-oriented linking of six research groups of the ELTE TTK with different scientific backgrounds and operating with outstanding results. The integrated theoretical, experimental and instrumental research team can realise the design, synthesis and extensive examination of peptide and protein-based nanosystems, in which the ß-reflecting spatial structure prone to aggregation is a common element. Biomolecules of this spatial structure include amyloid, spherical zipper, and adhesiv ß-fibres and filaments. They have both potential for material science (self-organised, compact nanosystems, biocompatible adhesives) and can address the serious challenges of life sciences such as Alzheimer’s (APP › ß1-42 aggregation) and Parkinson’s disease (aggregation of?-synuclein), diabetes mellitus (IAPP aggregation) or cancer type caused by underactive tumour suppressor p53 due to aggregation (Knowles 2014). The coordination of preparative, spectroscopic and crystallographic research in the six groups (Perczel), quantum chemistry (the Emperor) and mathematical (Grolmus) modelling, colloidal chemistry (Kiss), directed peptide and protein evolution tests (Pál) and in vivo genetic works (Vellai) allow the development of a focused yet ambitious research at ELTE. All of these applicants have been active and effective researchers for decades (cumulative data: >1000 announcements, >20000 references, >30 years of research experience abroad, >40 PhD students) who manage 5-20 in silico, in vitro and in vivo research support teams, lead MTA-ELTE research team, operate NMR, X-ray, ECD, VCD, AFM, SPR, SEM devices. Although hundreds of proteins have been described as spontaneously forming amyloids in physiological or slightly different circumstances, the molecular details and kinetic parameters of the processes are largely unknown — only occasional light scattering, fluorescence and EM data can be used. (In the course of our control studies prior to the preparation of the application plan, in the case of a variant of a peptide medicine (exenatide) used to cure type 2 diabetes, we discovered amyloid training that could be triggered by environmental changes — a unique test system that could be the ‘benchmark’ system of amyloid transformation). Using spectroscopic (ECD, VCD) and NMR methods, we intend to collect amino acid-specific information on details of amyloidal training, which can lead to the development of a “amyloid recognition” spectroscopy protocol. We intend to examine the protection against specific sequences by means of white octarography using “naturally” acilpeptide involved in the breakdown of the amyloid β-p... (English) | |||||||||||||||
| Property / summary: Amyloid aggregation is of outstanding biomedical, bio- and structural-chemical importance and has attracted continued interest over the past decades (B.S. Blumberg and D.C. Gajdusek for Kuru’s disease (1976) and S.B. Prusiner for prion heritage understanding (1997) received the Nobel Medical Prize). Scientific breakthroughs in this area can only be achieved if there is a high degree of synergy between researchers, critical numbers and resources. The necessary synthetic, biochemical, spectroscopic, modelling, bioanalytical and nanotechnology capacity is now available at ELTE TTK. Our focus is the development of protein test systems, the rational design, in vitro/vivo production and development of biocompatible nanosystems. In order to achieve our research goals, we intend to establish a centre of excellence, which can bring significant breakthroughs in the field due to the development of cooperation across the whole field of molecular biochemistry, combining six different approaches and six different perspectives. Understanding the spatial structure and dynamics of proteins is a research task that is of biomedical, social and economic importance beyond chemical curiosity and importance. Proteins can be identified in almost all parts of living organisms and function effectively, in accordance with their environment, as complex systems, with well-regulated protein-protein interactions in the background, and with oligo and polymerisation processes (Tory, Perczel, Nature Genetics 2014). However, these processes sometimes lead to aggregation and amyloid dead ends. The change in conformation, which has been diagnosed by Alois Alzheimer for more than 100 years but has not yet been accurately understood on a molecular level, is only one of the amyloid aggregations experienced in the process of ‘protein ageing’. Aggregation is a thermodynamically beneficiary (Perczel 2007), and its detailed understanding and use are central elements of our application. In addition to abnormal protein aggregation, a number of non-pathogenic aggregations are also known. Functional amyloids have played an important role in evolution in bacteria (Pseudomonas), cloak proteins (Plasmodium), spider silk, biofilms, adhesion proteins, etc.; they are distinguished by their stability, flexibility, tensile strength. Our application builds on the novel and goal-oriented linking of six research groups of the ELTE TTK with different scientific backgrounds and operating with outstanding results. The integrated theoretical, experimental and instrumental research team can realise the design, synthesis and extensive examination of peptide and protein-based nanosystems, in which the ß-reflecting spatial structure prone to aggregation is a common element. Biomolecules of this spatial structure include amyloid, spherical zipper, and adhesiv ß-fibres and filaments. They have both potential for material science (self-organised, compact nanosystems, biocompatible adhesives) and can address the serious challenges of life sciences such as Alzheimer’s (APP › ß1-42 aggregation) and Parkinson’s disease (aggregation of?-synuclein), diabetes mellitus (IAPP aggregation) or cancer type caused by underactive tumour suppressor p53 due to aggregation (Knowles 2014). The coordination of preparative, spectroscopic and crystallographic research in the six groups (Perczel), quantum chemistry (the Emperor) and mathematical (Grolmus) modelling, colloidal chemistry (Kiss), directed peptide and protein evolution tests (Pál) and in vivo genetic works (Vellai) allow the development of a focused yet ambitious research at ELTE. All of these applicants have been active and effective researchers for decades (cumulative data: >1000 announcements, >20000 references, >30 years of research experience abroad, >40 PhD students) who manage 5-20 in silico, in vitro and in vivo research support teams, lead MTA-ELTE research team, operate NMR, X-ray, ECD, VCD, AFM, SPR, SEM devices. Although hundreds of proteins have been described as spontaneously forming amyloids in physiological or slightly different circumstances, the molecular details and kinetic parameters of the processes are largely unknown — only occasional light scattering, fluorescence and EM data can be used. (In the course of our control studies prior to the preparation of the application plan, in the case of a variant of a peptide medicine (exenatide) used to cure type 2 diabetes, we discovered amyloid training that could be triggered by environmental changes — a unique test system that could be the ‘benchmark’ system of amyloid transformation). Using spectroscopic (ECD, VCD) and NMR methods, we intend to collect amino acid-specific information on details of amyloidal training, which can lead to the development of a “amyloid recognition” spectroscopy protocol. We intend to examine the protection against specific sequences by means of white octarography using “naturally” acilpeptide involved in the breakdown of the amyloid β-p... (English) / rank | |||||||||||||||
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| Property / summary: Amyloid aggregation is of outstanding biomedical, bio- and structural-chemical importance and has attracted continued interest over the past decades (B.S. Blumberg and D.C. Gajdusek for Kuru’s disease (1976) and S.B. Prusiner for prion heritage understanding (1997) received the Nobel Medical Prize). Scientific breakthroughs in this area can only be achieved if there is a high degree of synergy between researchers, critical numbers and resources. The necessary synthetic, biochemical, spectroscopic, modelling, bioanalytical and nanotechnology capacity is now available at ELTE TTK. Our focus is the development of protein test systems, the rational design, in vitro/vivo production and development of biocompatible nanosystems. In order to achieve our research goals, we intend to establish a centre of excellence, which can bring significant breakthroughs in the field due to the development of cooperation across the whole field of molecular biochemistry, combining six different approaches and six different perspectives. Understanding the spatial structure and dynamics of proteins is a research task that is of biomedical, social and economic importance beyond chemical curiosity and importance. Proteins can be identified in almost all parts of living organisms and function effectively, in accordance with their environment, as complex systems, with well-regulated protein-protein interactions in the background, and with oligo and polymerisation processes (Tory, Perczel, Nature Genetics 2014). However, these processes sometimes lead to aggregation and amyloid dead ends. The change in conformation, which has been diagnosed by Alois Alzheimer for more than 100 years but has not yet been accurately understood on a molecular level, is only one of the amyloid aggregations experienced in the process of ‘protein ageing’. Aggregation is a thermodynamically beneficiary (Perczel 2007), and its detailed understanding and use are central elements of our application. In addition to abnormal protein aggregation, a number of non-pathogenic aggregations are also known. Functional amyloids have played an important role in evolution in bacteria (Pseudomonas), cloak proteins (Plasmodium), spider silk, biofilms, adhesion proteins, etc.; they are distinguished by their stability, flexibility, tensile strength. Our application builds on the novel and goal-oriented linking of six research groups of the ELTE TTK with different scientific backgrounds and operating with outstanding results. The integrated theoretical, experimental and instrumental research team can realise the design, synthesis and extensive examination of peptide and protein-based nanosystems, in which the ß-reflecting spatial structure prone to aggregation is a common element. Biomolecules of this spatial structure include amyloid, spherical zipper, and adhesiv ß-fibres and filaments. They have both potential for material science (self-organised, compact nanosystems, biocompatible adhesives) and can address the serious challenges of life sciences such as Alzheimer’s (APP › ß1-42 aggregation) and Parkinson’s disease (aggregation of?-synuclein), diabetes mellitus (IAPP aggregation) or cancer type caused by underactive tumour suppressor p53 due to aggregation (Knowles 2014). The coordination of preparative, spectroscopic and crystallographic research in the six groups (Perczel), quantum chemistry (the Emperor) and mathematical (Grolmus) modelling, colloidal chemistry (Kiss), directed peptide and protein evolution tests (Pál) and in vivo genetic works (Vellai) allow the development of a focused yet ambitious research at ELTE. All of these applicants have been active and effective researchers for decades (cumulative data: >1000 announcements, >20000 references, >30 years of research experience abroad, >40 PhD students) who manage 5-20 in silico, in vitro and in vivo research support teams, lead MTA-ELTE research team, operate NMR, X-ray, ECD, VCD, AFM, SPR, SEM devices. Although hundreds of proteins have been described as spontaneously forming amyloids in physiological or slightly different circumstances, the molecular details and kinetic parameters of the processes are largely unknown — only occasional light scattering, fluorescence and EM data can be used. (In the course of our control studies prior to the preparation of the application plan, in the case of a variant of a peptide medicine (exenatide) used to cure type 2 diabetes, we discovered amyloid training that could be triggered by environmental changes — a unique test system that could be the ‘benchmark’ system of amyloid transformation). Using spectroscopic (ECD, VCD) and NMR methods, we intend to collect amino acid-specific information on details of amyloidal training, which can lead to the development of a “amyloid recognition” spectroscopy protocol. We intend to examine the protection against specific sequences by means of white octarography using “naturally” acilpeptide involved in the breakdown of the amyloid β-p... (English) / qualifier | |||||||||||||||
point in time: 9 February 2022
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Revision as of 18:46, 9 February 2022
Project Q3958249 in Hungary
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | Design and development of biocompatible nano- and mesosystems based on amyloid fibre formation |
Project Q3958249 in Hungary |
Statements
763,818,667 forint
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2,783,992.349 Euro
0.0027336256 Euro
15 December 2021
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1,018,424,889.333 forint
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74.999999 percent
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1 September 2017
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29 November 2021
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EÖTVÖS LORÁND TUDOMÁNYEGYETEM
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47°29'30.62"N, 18°58'44.15"E
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Az amiloid-aggregáció kiemelkedő orvosbiológiai, bio- és szerkezeti-kémiai jelentőséggel bír, az elmúlt évtizedek során folyamatos érdeklődés övezte (B.S. Blumberg és D.C. Gajdusek a Kuru-betegség (1976), S.B. Prusiner a prion-öröklődés megértésért (1997) kaptak orvosi Nobel-díjat). Tudományos áttörés ezen a területen csak nagyfokú kutatói szinergia, a kritikus létszám és erőforrás elérése esetén érhető el. Az ELTE TTK-n a szükséges szintetikus, biokémiai, spektroszkópiai, modellezési, bioanalitikai és nanotechnológiai kapacitás ma már rendelkezésre áll. Fókuszpontunkban a fehérje-tesztrendszerek fejlesztése, biokompatibilis nanorendszerek racionális tervezése, in vitro/vivo előállítása és fejlesztése áll. Kutatási céljaink elérése érdekében kiválósági központot kívánunk létrehozni, mely a molekuláris biokémia teljes területét átfogó együttműködés kialakítása miatt hozhat a témában jelentős áttörést, hat különböző megközelítés, hat különböző nézőpont egyesítésével. Fehérjék térszerkezetének és dinamikájának megértése, majd cél-racionális módosítása olyan kutatási feladat, mely a kémiai érdekességen és fontosságon túlmutatóan orvosbiológiai, társadalmi és gazdasági jelentőségű. Fehérjék az élő szervezetek szinte minden részében azonosíthatóak, hatékonyan, környezetükkel összhangban, komplex rendszerként működnek, a háttérben jól szabályozott fehérje-fehérje kölcsönhatásokkal, valamint oligo- és polimerizációs folyamatokkal (Tory, Perczel, Nature Genetics 2014). E folyamatok azonban néha aggregációs és amiloid zsákutcába torkollanak. Az Alois Alzheimer által több mint 100 éve diagnosztizált, ám molekuláris szinten máig pontosan meg nem értett konformációváltozás csak egy a „fehérje-öregedési” folyamatok során tapasztalt amiloid-aggregációk közül. Az aggregáció termodinamikailag kedvezményezett (Perczel 2007), részletes megértése és felhasználása pályázatunk központi eleme. A kóros fehérje-aggregáció mellett számos nem-patogén aggregáció is ismert. A funkcionális amiloidok fontos szerephez jutottak az evolúció során baktériumokban (Pseudomonas), köpenyfehérjeként (Plasmodium), pókselyem, biofilmek, adhéziós fehérjék, stb. képződésekor; kitüntetett stabilitásuk, rugalmasságuk, szakítószilárdságuk okán. Pályázatunk az ELTE TTK hat eltérő tudományos hátterű, kiemelkedő eredményességgel működő kutatócsoportjának újszerű, célorientált összekapcsolására épít. Az integrált elméleti, kísérletes és műszeres kutatói együttes olyan peptid és fehérje alapú nanorendszerek tervezését, szintézisét, széleskörű vizsgálatát tudja megvalósítani, melyben közös elem az aggregációra hajlamosító ß-redő térszerkezet. Az ilyen térszerkezetű biomolekulák közé tartoznak az amiloid, a szférikus zipzár, valamint az adhéziv ß-szálak és filamentumok. Ezek egyszerre hordoznak kiaknázható anyagtudományi lehetőségeket (önszerveződő, kompakt nanorendszerek, biokompatibilis ragasztók) és hozhatnak megoldást az élettudományok súlyos kihívásaira, mint az Alzheimer- (APP › ß1-42 aggregációja) és a Parkinson-kór (az ?-szinuklein aggregációja), a diabetes mellitus (az IAPP aggregációja), vagy az aggregáció miatt alulműködő tumorszuppresszor p53 fehérje okozta ráktípus (Knowles 2014). A hat csoportban folyó preparatív, spektroszkópiai és krisztallográfiai kutatások (Perczel), a kvantumkémiai (Császár) és a matematikai (Grolmusz) modellezés, a kolloidkémiai kísérletek (Kiss), az irányított peptid- és fehérjeevolúciós vizsgálódások (Pál), valamint az in vivo genetikai munkák (Vellai) összehangolása lehetővé teszi egy fókuszált, mégis nagy ívű kutatás kialakítását az ELTE-n. Az említett pályázók mindegyike évtizedek óta aktív és eredményes kutató (kumulatív adatok: >1000 közlemény, >20000 hivatkozás, >30 év külföldi kutatói tapasztalat, >40 PhD hallgató képzése), akik 5-20 fős in silico, in vitro és in vivo kutatásokat támogató csoportokat irányítanak, MTA-ELTE kutatócsoportot vezetnek, NMR, X-ray, ECD, VCD, AFM, SPR, SEM készülékeket üzemeltetnek. Noha már több száz fehérjéről leírták, hogy spontán módon amiloidot képeznek fiziológiás, vagy attól csak kissé eltérő körülmények között, a folyamatok molekuláris részletei, kinetikai paraméterei zömmel ismeretlenek - csupán eseti fényszórás, fluoreszcencia és EM adatokra támaszkodhatunk. (A pályázati terv megírását megelőző kontroll vizsgálataink során a 2-es típusú cukorbetegség gyógyításában használt peptid-gyógyszer (Exenatid) egy variánsa esetében környezeti változások által kiváltható amiloid képzést fedeztünk fel – egy unikális tesztrendszert mely az amiloid átalakulás „benchmark” rendszere lehet). Spektroszkópiai (ECD, VCD), valamint NMR módszerek alkalmazásával aminosav-specifikus információkat kívánunk gyűjteni az amiloid-képzés részleteiről, mely egy „amiloid-felismerő” spektroszkópiai protokoll fejlesztéséhez vezethet el. Fehérjekrisztallográfiai módszerekkel a konkrét szekvenciák elleni védekezést a „természettől ellesve” kívánjuk vizsgálni, az amiloid ß-peptid lebontásában részt vevő acilpeptid (Hungarian)
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Amyloid aggregation is of outstanding biomedical, bio- and structural-chemical importance and has attracted continued interest over the past decades (B.S. Blumberg and D.C. Gajdusek for Kuru’s disease (1976) and S.B. Prusiner for prion heritage understanding (1997) received the Nobel Medical Prize). Scientific breakthroughs in this area can only be achieved if there is a high degree of synergy between researchers, critical numbers and resources. The necessary synthetic, biochemical, spectroscopic, modelling, bioanalytical and nanotechnology capacity is now available at ELTE TTK. Our focus is the development of protein test systems, the rational design, in vitro/vivo production and development of biocompatible nanosystems. In order to achieve our research goals, we intend to establish a centre of excellence, which can bring significant breakthroughs in the field due to the development of cooperation across the whole field of molecular biochemistry, combining six different approaches and six different perspectives. Understanding the spatial structure and dynamics of proteins is a research task that is of biomedical, social and economic importance beyond chemical curiosity and importance. Proteins can be identified in almost all parts of living organisms and function effectively, in accordance with their environment, as complex systems, with well-regulated protein-protein interactions in the background, and with oligo and polymerisation processes (Tory, Perczel, Nature Genetics 2014). However, these processes sometimes lead to aggregation and amyloid dead ends. The change in conformation, which has been diagnosed by Alois Alzheimer for more than 100 years but has not yet been accurately understood on a molecular level, is only one of the amyloid aggregations experienced in the process of ‘protein ageing’. Aggregation is a thermodynamically beneficiary (Perczel 2007), and its detailed understanding and use are central elements of our application. In addition to abnormal protein aggregation, a number of non-pathogenic aggregations are also known. Functional amyloids have played an important role in evolution in bacteria (Pseudomonas), cloak proteins (Plasmodium), spider silk, biofilms, adhesion proteins, etc.; they are distinguished by their stability, flexibility, tensile strength. Our application builds on the novel and goal-oriented linking of six research groups of the ELTE TTK with different scientific backgrounds and operating with outstanding results. The integrated theoretical, experimental and instrumental research team can realise the design, synthesis and extensive examination of peptide and protein-based nanosystems, in which the ß-reflecting spatial structure prone to aggregation is a common element. Biomolecules of this spatial structure include amyloid, spherical zipper, and adhesiv ß-fibres and filaments. They have both potential for material science (self-organised, compact nanosystems, biocompatible adhesives) and can address the serious challenges of life sciences such as Alzheimer’s (APP › ß1-42 aggregation) and Parkinson’s disease (aggregation of?-synuclein), diabetes mellitus (IAPP aggregation) or cancer type caused by underactive tumour suppressor p53 due to aggregation (Knowles 2014). The coordination of preparative, spectroscopic and crystallographic research in the six groups (Perczel), quantum chemistry (the Emperor) and mathematical (Grolmus) modelling, colloidal chemistry (Kiss), directed peptide and protein evolution tests (Pál) and in vivo genetic works (Vellai) allow the development of a focused yet ambitious research at ELTE. All of these applicants have been active and effective researchers for decades (cumulative data: >1000 announcements, >20000 references, >30 years of research experience abroad, >40 PhD students) who manage 5-20 in silico, in vitro and in vivo research support teams, lead MTA-ELTE research team, operate NMR, X-ray, ECD, VCD, AFM, SPR, SEM devices. Although hundreds of proteins have been described as spontaneously forming amyloids in physiological or slightly different circumstances, the molecular details and kinetic parameters of the processes are largely unknown — only occasional light scattering, fluorescence and EM data can be used. (In the course of our control studies prior to the preparation of the application plan, in the case of a variant of a peptide medicine (exenatide) used to cure type 2 diabetes, we discovered amyloid training that could be triggered by environmental changes — a unique test system that could be the ‘benchmark’ system of amyloid transformation). Using spectroscopic (ECD, VCD) and NMR methods, we intend to collect amino acid-specific information on details of amyloidal training, which can lead to the development of a “amyloid recognition” spectroscopy protocol. We intend to examine the protection against specific sequences by means of white octarography using “naturally” acilpeptide involved in the breakdown of the amyloid β-p... (English)
9 February 2022
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Budapest, Budapest
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Identifiers
VEKOP-2.3.2-16-2017-00014
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