Project acronym CentSatRegFunc
Project Dissecting the function and regulation of centriolar satellites: key regulators of the centrosome/cilium complex
Researcher (PI) Elif Nur Firat Karalar
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), LS3, ERC-2015-STG
Summary Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia.
Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.
Summary
Centrosomes are the main microtubule-organizing centers of animal cells. They influence the morphology of the microtubule cytoskeleton and function as the base of primary cilium, a nexus for important signaling pathways. Structural and functional defects in centrosome/cilium complex cause a variety of human diseases including cancer, ciliopathies and microcephaly. To understand the relationship between human diseases and centrosome/cilium abnormalities, it is essential to elucidate the biogenesis of centrosome/cilium complex and the control mechanisms that regulate their structure and function. To tackle these fundamental problems, we will dissect the function and regulation of centriolar satellites, the array of granules that localize around the centrosome/cilium complex in mammalian cells. Only recently interest in the satellites has grown because mutations affecting satellite components were shown to cause ciliopathies, microcephaly and schizophrenia.
Remarkably, many centrosome/cilium proteins localize to these structures and we lack understanding of when, why and how these proteins localize to satellites. The central hypothesis of this grant is that satellites ensure proper centrosome/cilium complex structure and function by acting as transit paths for modification, assembly, storage, stability and trafficking of centrosome/cilium proteins. In Aim 1, we will identify the nature of regulatory and molecular relationship between satellites and the centrosome/cilium complex. In Aim 2, we will elucidate the role of satellites in proteostasis of centrosome/cilium proteins. In Aim 3, we will investigate the functional significance of satellite-localization of centrosome/cilium proteins during processes that go awry in human disease. Using a multidisciplinary approach, the proposed research will expand our knowledge of the spatiotemporal regulation of the centrosome/cilium complex and provide new insights into pathogenesis of ciliopathies and primary microcephaly.
Max ERC Funding
1 499 819 €
Duration
Start date: 2016-06-01, End date: 2021-05-31
Project acronym COSMOS
Project Computational Simulations of MOFs for Gas Separations
Researcher (PI) Seda Keskin Avci
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), PE8, ERC-2017-STG
Summary Metal organic frameworks (MOFs) are recently considered as new fascinating nanoporous materials. MOFs have very large surface areas, high porosities, various pore sizes/shapes, chemical functionalities and good thermal/chemical stabilities. These properties make MOFs highly promising for gas separation applications. Thousands of MOFs have been synthesized in the last decade. The large number of available MOFs creates excellent opportunities to develop energy-efficient gas separation technologies. On the other hand, it is very challenging to identify the best materials for each gas separation of interest. Considering the continuous rapid increase in the number of synthesized materials, it is practically not possible to test each MOF using purely experimental manners. Highly accurate computational methods are required to identify the most promising MOFs to direct experimental efforts, time and resources to those materials. In this project, I will build a complete MOF library and use molecular simulations to assess adsorption and diffusion properties of gas mixtures in MOFs. Results of simulations will be used to predict adsorbent and membrane properties of MOFs for scientifically and technologically important gas separation processes such as CO2/CH4 (natural gas purification), CO2/N2 (flue gas separation), CO2/H2, CH4/H2 and N2/H2 (hydrogen recovery). I will obtain the fundamental, atomic-level insights into the common features of the top-performing MOFs and establish structure-performance relations. These relations will be used as guidelines to computationally design new MOFs with outstanding separation performances for CO2 capture and H2 recovery. These new MOFs will be finally synthesized in the lab scale and tested as adsorbents and membranes under practical operating conditions for each gas separation of interest. Combining a multi-stage computational approach with experiments, this project will lead to novel, efficient gas separation technologies based on MOFs.
Summary
Metal organic frameworks (MOFs) are recently considered as new fascinating nanoporous materials. MOFs have very large surface areas, high porosities, various pore sizes/shapes, chemical functionalities and good thermal/chemical stabilities. These properties make MOFs highly promising for gas separation applications. Thousands of MOFs have been synthesized in the last decade. The large number of available MOFs creates excellent opportunities to develop energy-efficient gas separation technologies. On the other hand, it is very challenging to identify the best materials for each gas separation of interest. Considering the continuous rapid increase in the number of synthesized materials, it is practically not possible to test each MOF using purely experimental manners. Highly accurate computational methods are required to identify the most promising MOFs to direct experimental efforts, time and resources to those materials. In this project, I will build a complete MOF library and use molecular simulations to assess adsorption and diffusion properties of gas mixtures in MOFs. Results of simulations will be used to predict adsorbent and membrane properties of MOFs for scientifically and technologically important gas separation processes such as CO2/CH4 (natural gas purification), CO2/N2 (flue gas separation), CO2/H2, CH4/H2 and N2/H2 (hydrogen recovery). I will obtain the fundamental, atomic-level insights into the common features of the top-performing MOFs and establish structure-performance relations. These relations will be used as guidelines to computationally design new MOFs with outstanding separation performances for CO2 capture and H2 recovery. These new MOFs will be finally synthesized in the lab scale and tested as adsorbents and membranes under practical operating conditions for each gas separation of interest. Combining a multi-stage computational approach with experiments, this project will lead to novel, efficient gas separation technologies based on MOFs.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-10-01, End date: 2022-09-30
Project acronym VASCULARGROWTH
Project Bioengineering prediction of three-dimensional vascular growth and remodeling in embryonic great-vessel development
Researcher (PI) Kerem Pekkan
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), PE8, ERC-2012-StG_20111012
Summary Globally 1 in 100 children are born with significant congenital heart defects (CHD), representing either new genetic mutations or epigenetic insults that alter cardiac morphogenesis in utero. Embryonic CV systems dynamically regulate structure and function over very short time periods throughout morphogenesis and that biomechanical loading conditions within the heart and great-vessels alter morphogenesis and gene expression. This proposal has structured around a common goal of developing a comprehensive and predictive understanding of the biomechanics and regulation of great-vessel development and its plasticity in response to clinically relevant epigenetic changes in loading conditions. Biomechanical regulation of vascular morphogenesis, including potential aortic arch (AA) reversibility or plasticity after epigenetic events relevant to human CHD are investigated using multimodal experiments in the chick embryo that investigate normal AA growth and remodeling, microsurgical instrumentation that alter ventricular and vascular blood flow loading during critical periods in AA morphogenesis. WP 1 establishes our novel optimization framework, incorporates basic input/output in vivo data sets, and validates. In WP 2 and 3 the numerical models for perturbed biomechanical environment and incorporate new objective functions that have in vivo structural data inputs and predict changes in structure and function. WP 4 incorporates candidate genes and pathways during normal and experimentally altered AA morphogenesis. This proposal develops and validates the first in vivo morphomechanics-integrated three-dimensional mathematical models of AA growth and remodeling that can predict normal growth patterns and abnormal vascular adaptations common in CHD. Multidisciplinary application of bioengineering principles to CHD is likely to provide novel insights and paradigms towards our long-term goal of optimizing CHD interventions, outcomes, and the potential for preventive strategies.
Summary
Globally 1 in 100 children are born with significant congenital heart defects (CHD), representing either new genetic mutations or epigenetic insults that alter cardiac morphogenesis in utero. Embryonic CV systems dynamically regulate structure and function over very short time periods throughout morphogenesis and that biomechanical loading conditions within the heart and great-vessels alter morphogenesis and gene expression. This proposal has structured around a common goal of developing a comprehensive and predictive understanding of the biomechanics and regulation of great-vessel development and its plasticity in response to clinically relevant epigenetic changes in loading conditions. Biomechanical regulation of vascular morphogenesis, including potential aortic arch (AA) reversibility or plasticity after epigenetic events relevant to human CHD are investigated using multimodal experiments in the chick embryo that investigate normal AA growth and remodeling, microsurgical instrumentation that alter ventricular and vascular blood flow loading during critical periods in AA morphogenesis. WP 1 establishes our novel optimization framework, incorporates basic input/output in vivo data sets, and validates. In WP 2 and 3 the numerical models for perturbed biomechanical environment and incorporate new objective functions that have in vivo structural data inputs and predict changes in structure and function. WP 4 incorporates candidate genes and pathways during normal and experimentally altered AA morphogenesis. This proposal develops and validates the first in vivo morphomechanics-integrated three-dimensional mathematical models of AA growth and remodeling that can predict normal growth patterns and abnormal vascular adaptations common in CHD. Multidisciplinary application of bioengineering principles to CHD is likely to provide novel insights and paradigms towards our long-term goal of optimizing CHD interventions, outcomes, and the potential for preventive strategies.
Max ERC Funding
1 995 140 €
Duration
Start date: 2013-01-01, End date: 2019-07-31
