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 INFIBRENANOSTRUCTURE
Project Fabrication and characterization of dielectric encapsulated millions of ordered kilometer-long nanostructures and their applications
Researcher (PI) Mehmet Bayindir
Host Institution (HI) BILKENT UNIVERSITESI VAKIF
Call Details Starting Grant (StG), PE5, ERC-2012-StG_20111012
Summary The objective of this project is the realization of a radically new nanowire fabrication technique, and exploration of its potential for nanowire based science and technology. The proposed method involves fabrication of unusually long, ordered nanowire and nanotube arrays in macroscopic fibres by means of an iterative thermal co-drawing process. Starting with a macroscopic rod with an annular hole tightly fitted with another rod of another compatible material, by successive thermal drawing we obtain arrays of nanowires embedded in fibres. With the method, wide range of materials, e.g. semiconductors, polymers, metals, can be turned into ordered nanorods, nanowires, nanotubes in various cross-sectional geometries. Main challenges are the thermal drawing steps that require critical matching of the viscoelastic properties of the protective cover with the encapsulated materials, and the liquid instability problems and phase intermixing with higher temperatures and smaller feature sizes that require high thermal and mechanical precision. Initially, fabrication by drawing will begin with soft amorphous semiconductors, phase change materials, polymers of interest in high temperature polymers, followed by a wider range of materials, low melting temperature metals, metals and common semiconductors (Si, Ge) in silica glass matrices. In this way nanowires that are ordered, easily accessible and hermetically sealed in a dielectric encapsulation will be obtained in high volumes. Potentially, these nanowires are advantages over on-chip nanowires in building flexible out of plane geometries, light weight, wearable and disposable devices. Ultimately, attaining ordered arrays of 1-D nanostructures in an extended flexible fibre with high yields will facilitate sought-after but up-to-now difficult applications such as the large area nanowire electronics and photonics, nanowire based scalable phase-change memory, nanowire photovoltaics, and emerging cell-nanowire interfacing.
Summary
The objective of this project is the realization of a radically new nanowire fabrication technique, and exploration of its potential for nanowire based science and technology. The proposed method involves fabrication of unusually long, ordered nanowire and nanotube arrays in macroscopic fibres by means of an iterative thermal co-drawing process. Starting with a macroscopic rod with an annular hole tightly fitted with another rod of another compatible material, by successive thermal drawing we obtain arrays of nanowires embedded in fibres. With the method, wide range of materials, e.g. semiconductors, polymers, metals, can be turned into ordered nanorods, nanowires, nanotubes in various cross-sectional geometries. Main challenges are the thermal drawing steps that require critical matching of the viscoelastic properties of the protective cover with the encapsulated materials, and the liquid instability problems and phase intermixing with higher temperatures and smaller feature sizes that require high thermal and mechanical precision. Initially, fabrication by drawing will begin with soft amorphous semiconductors, phase change materials, polymers of interest in high temperature polymers, followed by a wider range of materials, low melting temperature metals, metals and common semiconductors (Si, Ge) in silica glass matrices. In this way nanowires that are ordered, easily accessible and hermetically sealed in a dielectric encapsulation will be obtained in high volumes. Potentially, these nanowires are advantages over on-chip nanowires in building flexible out of plane geometries, light weight, wearable and disposable devices. Ultimately, attaining ordered arrays of 1-D nanostructures in an extended flexible fibre with high yields will facilitate sought-after but up-to-now difficult applications such as the large area nanowire electronics and photonics, nanowire based scalable phase-change memory, nanowire photovoltaics, and emerging cell-nanowire interfacing.
Max ERC Funding
1 495 400 €
Duration
Start date: 2012-10-01, End date: 2017-09-30
Project acronym METARNAFLAMMATION
Project The RNA bridge between IRE-1 and PKR leading to metaflammation: discovery and intervention in atherosclerosis
Researcher (PI) Ebru Erbay
Host Institution (HI) BILKENT UNIVERSITESI VAKIF
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary A close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its’ deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response known as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive.
Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a central paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways.
Summary
A close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its’ deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response known as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive.
Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a central paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways.
Max ERC Funding
1 362 921 €
Duration
Start date: 2014-01-01, End date: 2018-06-30
Project acronym NEOGENE
Project Archaeogenomic analysis of genetic and cultural interactions in Neolithic Anatolian societies
Researcher (PI) Mehmet SOMEL
Host Institution (HI) MIDDLE EAST TECHNICAL UNIVERSITY
Call Details Consolidator Grant (CoG), SH6, ERC-2017-COG
Summary The Neolithic Transition in the Near East (c.10,000-6,000 BC) was a period of singular sociocultural change, when societies adopted sedentary life and agriculture for the first time in human history. This project will jointly use genomic and quantitative cultural data to explore Transition societies’ organisation, interactions, and their social and demographic evolution in time. (1) We will start by dissecting social structures within Neolithic communities in Anatolia, studying the role of kinship, postmarital residence customs, and endogamy. For this end, we will produce genotype data for c.250 individuals interred within five Pre-Pottery and Pottery Neolithic villages in South East and Central Anatolia, and analyse genomic relatedness patterns in the context of bioarchaeological similarity (e.g. by measuring genetic relatedness among Çatalhöyük individuals buried within the same house over generations). (2) We will study the means of cultural interaction among Near Eastern Neolithic societies by documenting which cultural traits -from skull removal customs to pottery- were most likely propagated through emulation and acculturation, and which ones by gene flow, when and where. Here we will produce whole genome data, compile genomic and material culture similarity matrices for >30 Near Eastern pre-Neolithic and Neolithic populations, and develop frameworks for integrated analysis of quantitative material culture and genomic similarity among populations (also including obsidian and sheep exchange connections as factors). The data will be analysed on multiple levels: within regions, interregional, and diachronic. (3) The work will conclude by examining the evolution of social organisation and population interaction patterns through the Neolithic Transition. While enriching and revising current Transition models, the project will set precedents for employing archaeogenomics to study social structures and for systematic co-analysis of genomic and archaeological data.
Summary
The Neolithic Transition in the Near East (c.10,000-6,000 BC) was a period of singular sociocultural change, when societies adopted sedentary life and agriculture for the first time in human history. This project will jointly use genomic and quantitative cultural data to explore Transition societies’ organisation, interactions, and their social and demographic evolution in time. (1) We will start by dissecting social structures within Neolithic communities in Anatolia, studying the role of kinship, postmarital residence customs, and endogamy. For this end, we will produce genotype data for c.250 individuals interred within five Pre-Pottery and Pottery Neolithic villages in South East and Central Anatolia, and analyse genomic relatedness patterns in the context of bioarchaeological similarity (e.g. by measuring genetic relatedness among Çatalhöyük individuals buried within the same house over generations). (2) We will study the means of cultural interaction among Near Eastern Neolithic societies by documenting which cultural traits -from skull removal customs to pottery- were most likely propagated through emulation and acculturation, and which ones by gene flow, when and where. Here we will produce whole genome data, compile genomic and material culture similarity matrices for >30 Near Eastern pre-Neolithic and Neolithic populations, and develop frameworks for integrated analysis of quantitative material culture and genomic similarity among populations (also including obsidian and sheep exchange connections as factors). The data will be analysed on multiple levels: within regions, interregional, and diachronic. (3) The work will conclude by examining the evolution of social organisation and population interaction patterns through the Neolithic Transition. While enriching and revising current Transition models, the project will set precedents for employing archaeogenomics to study social structures and for systematic co-analysis of genomic and archaeological data.
Max ERC Funding
2 556 250 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym UrbanOccupationsOETR
Project Industrialisation and Urban Growth from the mid-nineteenth century Ottoman Empire to Contemporary Turkey in a Comparative Perspective, 1850-2000
Researcher (PI) Mustafa Erdem Kabadayi
Host Institution (HI) KOC UNIVERSITY
Call Details Starting Grant (StG), SH6, ERC-2015-STG
Summary This project aims to overcome historiographical and disciplinary limitations in social and economic history, historical geography and urban studies for the Ottoman Empire and the Republic of Turkey. The chosen long-term Ottoman/Turkish perspective is intended to facilitate comparative approaches so as to overcome the limitations of national historiographies. By extending the analysis up to 2000 the project also challenges the disciplinary divide between economic history, economics and urban studies in research on Turkey. To pursue these multiple goals the project will adopt both an inter-disciplinary approach and a comparative perspective. Throughout the project the focus will be on the dynamics of industrialisation, urbanisation and their accompanying changes in occupational structures and residential and migration patterns.
To be able to contextualise and compare changes in occupational structure and urban growth trajectories across time and space, solid and detailed datasets of occupational structure and historical demographics for a very large part of the Ottoman Empire in the 19th century and for the entire Turkey in the 20th century will be constructed. This project is an attempt at bringing Ottoman/Turkish history into the newly emerging field of digital humanities. It will use advanced techniques of spatial data and multiple correspondence analysis in conjuncture to answer long debated research questions and to formulate and work on new ones by taking an unprecedented step forward toward establishing a digital research infrastructure for the social and economic history of the Ottoman Empire and the Republic of Turkey. This project will re-define industrialisation in its connection with urbanisation from a spatiotemporal analytical perspective for Anatolia and the Southeast Europe to ask time and space specific questions about, simultaneity and geographical convergence of Eurasian economic development since 1850.
Summary
This project aims to overcome historiographical and disciplinary limitations in social and economic history, historical geography and urban studies for the Ottoman Empire and the Republic of Turkey. The chosen long-term Ottoman/Turkish perspective is intended to facilitate comparative approaches so as to overcome the limitations of national historiographies. By extending the analysis up to 2000 the project also challenges the disciplinary divide between economic history, economics and urban studies in research on Turkey. To pursue these multiple goals the project will adopt both an inter-disciplinary approach and a comparative perspective. Throughout the project the focus will be on the dynamics of industrialisation, urbanisation and their accompanying changes in occupational structures and residential and migration patterns.
To be able to contextualise and compare changes in occupational structure and urban growth trajectories across time and space, solid and detailed datasets of occupational structure and historical demographics for a very large part of the Ottoman Empire in the 19th century and for the entire Turkey in the 20th century will be constructed. This project is an attempt at bringing Ottoman/Turkish history into the newly emerging field of digital humanities. It will use advanced techniques of spatial data and multiple correspondence analysis in conjuncture to answer long debated research questions and to formulate and work on new ones by taking an unprecedented step forward toward establishing a digital research infrastructure for the social and economic history of the Ottoman Empire and the Republic of Turkey. This project will re-define industrialisation in its connection with urbanisation from a spatiotemporal analytical perspective for Anatolia and the Southeast Europe to ask time and space specific questions about, simultaneity and geographical convergence of Eurasian economic development since 1850.
Max ERC Funding
1 497 500 €
Duration
Start date: 2016-10-01, End date: 2021-09-30
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
