Project acronym 3DBrainStrom
Project Brain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines
Researcher (PI) Ronit Satchi Fainaro
Host Institution (HI) TEL AVIV UNIVERSITY
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Summary
Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors.
This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.
Max ERC Funding
2 353 125 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym 5D-NanoTrack
Project Five-Dimensional Localization Microscopy for Sub-Cellular Dynamics
Researcher (PI) Yoav SHECHTMAN
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), PE7, ERC-2018-STG
Summary The sub-cellular processes that control the most critical aspects of life occur in three-dimensions (3D), and are intrinsically dynamic. While super-resolution microscopy has revolutionized cellular imaging in recent years, our current capability to observe the dynamics of life on the nanoscale is still extremely limited, due to inherent trade-offs between spatial, temporal and spectral resolution using existing approaches.
We propose to develop and demonstrate an optical microscopy methodology that would enable live sub-cellular observation in unprecedented detail. Making use of multicolor 3D point-spread-function (PSF) engineering, a technique I have recently developed, we will be able to simultaneously track multiple markers inside live cells, at high speed and in five-dimensions (3D, time, and color).
Multicolor 3D PSF engineering holds the potential of being a uniquely powerful method for 5D tracking. However, it is not yet applicable to live-cell imaging, due to significant bottlenecks in optical engineering and signal processing, which we plan to overcome in this project. Importantly, we will also demonstrate the efficacy of our method using a challenging biological application: real-time visualization of chromatin dynamics - the spatiotemporal organization of DNA. This is a highly suitable problem due to its fundamental importance, its role in a variety of cellular processes, and the lack of appropriate tools for studying it.
The project is divided into 3 aims:
1. Technology development: diffractive-element design for multicolor 3D PSFs.
2. System design: volumetric tracking of dense emitters.
3. Live-cell measurements: chromatin dynamics.
Looking ahead, here we create the imaging tools that pave the way towards the holy grail of chromatin visualization: dynamic observation of the 3D positions of the ~3 billion DNA base-pairs in a live human cell. Beyond that, our results will be applicable to numerous 3D micro/nanoscale tracking applications.
Summary
The sub-cellular processes that control the most critical aspects of life occur in three-dimensions (3D), and are intrinsically dynamic. While super-resolution microscopy has revolutionized cellular imaging in recent years, our current capability to observe the dynamics of life on the nanoscale is still extremely limited, due to inherent trade-offs between spatial, temporal and spectral resolution using existing approaches.
We propose to develop and demonstrate an optical microscopy methodology that would enable live sub-cellular observation in unprecedented detail. Making use of multicolor 3D point-spread-function (PSF) engineering, a technique I have recently developed, we will be able to simultaneously track multiple markers inside live cells, at high speed and in five-dimensions (3D, time, and color).
Multicolor 3D PSF engineering holds the potential of being a uniquely powerful method for 5D tracking. However, it is not yet applicable to live-cell imaging, due to significant bottlenecks in optical engineering and signal processing, which we plan to overcome in this project. Importantly, we will also demonstrate the efficacy of our method using a challenging biological application: real-time visualization of chromatin dynamics - the spatiotemporal organization of DNA. This is a highly suitable problem due to its fundamental importance, its role in a variety of cellular processes, and the lack of appropriate tools for studying it.
The project is divided into 3 aims:
1. Technology development: diffractive-element design for multicolor 3D PSFs.
2. System design: volumetric tracking of dense emitters.
3. Live-cell measurements: chromatin dynamics.
Looking ahead, here we create the imaging tools that pave the way towards the holy grail of chromatin visualization: dynamic observation of the 3D positions of the ~3 billion DNA base-pairs in a live human cell. Beyond that, our results will be applicable to numerous 3D micro/nanoscale tracking applications.
Max ERC Funding
1 802 500 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym AEROBIC
Project Assessing the Effects of Rising O2 on Biogeochemical Cycles: Integrated Laboratory Experiments and Numerical Simulations
Researcher (PI) Itay Halevy
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), PE10, ERC-2013-StG
Summary The rise of atmospheric O2 ~2,500 million years ago is one of the most profound transitions in Earth's history. Yet, despite its central role in shaping Earth's surface environment, the cause for the rise of O2 remains poorly understood. Tight coupling between the O2 cycle and the biogeochemical cycles of redox-active elements, such as C, Fe and S, implies radical changes in these cycles before, during and after the rise of O2. These changes, too, are incompletely understood, but have left valuable information encoded in the geological record. This information has been qualitatively interpreted, leaving many aspects of the rise of O2, including its causes and constraints on ocean chemistry before and after it, topics of ongoing research and debate. Here, I outline a research program to address this fundamental question in geochemical Earth systems evolution. The inherently interdisciplinary program uniquely integrates laboratory experiments, numerical models, geological observations, and geochemical analyses. Laboratory experiments and geological observations will constrain unknown parameters of the early biogeochemical cycles, and, in combination with field studies, will validate and refine the use of paleoenvironmental proxies. The insight gained will be used to develop detailed models of the coupled biogeochemical cycles, which will themselves be used to quantitatively understand the events surrounding the rise of O2, and to illuminate the dynamics of elemental cycles in the early oceans.
This program is expected to yield novel, quantitative insight into these important events in Earth history and to have a major impact on our understanding of early ocean chemistry and the rise of O2. An ERC Starting Grant will enable me to use the excellent experimental and computational facilities at my disposal, to access the outstanding human resource at the Weizmann Institute of Science, and to address one of the major open questions in modern geochemistry.
Summary
The rise of atmospheric O2 ~2,500 million years ago is one of the most profound transitions in Earth's history. Yet, despite its central role in shaping Earth's surface environment, the cause for the rise of O2 remains poorly understood. Tight coupling between the O2 cycle and the biogeochemical cycles of redox-active elements, such as C, Fe and S, implies radical changes in these cycles before, during and after the rise of O2. These changes, too, are incompletely understood, but have left valuable information encoded in the geological record. This information has been qualitatively interpreted, leaving many aspects of the rise of O2, including its causes and constraints on ocean chemistry before and after it, topics of ongoing research and debate. Here, I outline a research program to address this fundamental question in geochemical Earth systems evolution. The inherently interdisciplinary program uniquely integrates laboratory experiments, numerical models, geological observations, and geochemical analyses. Laboratory experiments and geological observations will constrain unknown parameters of the early biogeochemical cycles, and, in combination with field studies, will validate and refine the use of paleoenvironmental proxies. The insight gained will be used to develop detailed models of the coupled biogeochemical cycles, which will themselves be used to quantitatively understand the events surrounding the rise of O2, and to illuminate the dynamics of elemental cycles in the early oceans.
This program is expected to yield novel, quantitative insight into these important events in Earth history and to have a major impact on our understanding of early ocean chemistry and the rise of O2. An ERC Starting Grant will enable me to use the excellent experimental and computational facilities at my disposal, to access the outstanding human resource at the Weizmann Institute of Science, and to address one of the major open questions in modern geochemistry.
Max ERC Funding
1 472 690 €
Duration
Start date: 2013-09-01, End date: 2018-08-31
Project acronym BARCODE DIAGNOSTICS
Project Next-Generation Personalized Diagnostic Nanotechnologies for Predicting Response to Cancer Medicine
Researcher (PI) Avraham Dror Schroeder
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate.
Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale.
In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine.
To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells.
To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments.
We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.
Summary
Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate.
Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale.
In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine.
To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells.
To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments.
We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.
Max ERC Funding
1 499 250 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym BARINAFLD
Project Using Bariatric Surgery to Discover Weight-Loss Independent Mechanisms Leading to the Reversal of Fatty Liver Disease
Researcher (PI) Danny Ben-Zvi
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes.
The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD.
In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery.
I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.
Summary
Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes.
The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD.
In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery.
I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.
Max ERC Funding
1 499 354 €
Duration
Start date: 2018-11-01, End date: 2023-10-31
Project acronym BETATOBETA
Project The molecular basis of pancreatic beta cell replication
Researcher (PI) Yuval Dor
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.
Summary
A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.
Max ERC Funding
1 445 000 €
Duration
Start date: 2010-09-01, End date: 2015-08-31
Project acronym BisProt
Project Developing Multispecific Biological Agents that Target Tumor Neovasculature for Cancer Imaging and Therapy
Researcher (PI) Niv Papo
Host Institution (HI) BEN-GURION UNIVERSITY OF THE NEGEV
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.
Summary
The dysregulation of signaling pathways that mediate cell proliferation, survival and migration is an underlying cause of many cancers. In particular, dysregulation and over-expression of avb3 integrin, membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase-14, MMP14) and vascular endothelial growth factor receptor-2 (VEGFR2) correlate with poor prognosis in many human tumors, making these proteins attractive targets for therapeutic intervention. Numerous papers have demonstrated the cross-talk between biological processes mediated by αvβ3 integrins, MT1-MMP, VEGFR2, and their ligands, particularly pathways responsible for angiogenesis. Dual-specific proteins that can target and inhibit the activity of the above multiple receptors therefore have superior potential to single-targeted agents due to differential expression of these disease markers in different patients and the ability of this expression to change over time. Most currently available bispecific protein therapeutics comprise antibodies (Abs) or antibody fragments. The new approach proposed here entails rational and combinatorial methods for engineering multispecificity into small peptides and natural protein ligands to function as non-immunoglobulin alternatives to antibodies. In this innovative approach to creating dual-specific proteins, an additional functionality is introduced into a small peptide or into a natural protein ligand to complement its existing biological properties. We predict that this approach will form a major part of a highly effective strategy for creating ligand-based multispecific receptor inhibitors and molecular tools for protein recognition. We envision that protein variants generated from these efforts will promote the next generation of therapeutics including, but not limited to, molecular imaging agents, targeted drug delivery agents, and selective tissue targeting probes.
Max ERC Funding
1 625 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym BNYQ
Project Breaking the Nyquist Barrier: A New Paradigm in Data Conversion and Transmission
Researcher (PI) Yonina Eldar
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Consolidator Grant (CoG), PE7, ERC-2014-CoG
Summary Digital signal processing (DSP) is a revolutionary paradigm shift enabling processing of physical data in the digital domain where design and implementation are considerably simplified. However, state-of-the-art analog-to-digital convertors (ADCs) preclude high-rate wideband sampling and processing with low cost and energy consumption, presenting a major bottleneck. This is mostly due to a traditional assumption that sampling must be performed at the Nyquist rate, that is, twice the signal bandwidth. Modern applications including communications, medical imaging, radar and more use signals with high bandwidth, resulting in prohibitively large Nyquist rates.
Our ambitious goal is to introduce a paradigm shift in ADC design that will enable systems capable of low-rate, wideband sensing and low-rate DSP.
While DSP has a rich history in exploiting structure to reduce dimensionality and perform efficient parameter extraction, current ADCs do not exploit such knowledge.
We challenge current practice that separates the sampling stage from the processing stage and exploit structure in analog signals already in the ADC, to drastically reduce the sampling and processing rates.
Our preliminary data shows that this allows substantial savings in sampling and processing rates --- we show rate reduction of 1/28 in ultrasound imaging, and 1/30 in radar detection.
To achieve our overreaching goal we focus on three interconnected objectives -- developing the 1) theory 2) hardware and 3) applications of sub-Nyquist sampling.
Our methodology ties together two areas on the frontier of signal processing: compressed sensing (CS), focused on finite length vectors, and analog sampling. Our research plan also inherently relies on advances in several other important areas within signal processing and combines multi-disciplinary research at the intersection of signal processing, information theory, optimization, estimation theory and hardware design.
Summary
Digital signal processing (DSP) is a revolutionary paradigm shift enabling processing of physical data in the digital domain where design and implementation are considerably simplified. However, state-of-the-art analog-to-digital convertors (ADCs) preclude high-rate wideband sampling and processing with low cost and energy consumption, presenting a major bottleneck. This is mostly due to a traditional assumption that sampling must be performed at the Nyquist rate, that is, twice the signal bandwidth. Modern applications including communications, medical imaging, radar and more use signals with high bandwidth, resulting in prohibitively large Nyquist rates.
Our ambitious goal is to introduce a paradigm shift in ADC design that will enable systems capable of low-rate, wideband sensing and low-rate DSP.
While DSP has a rich history in exploiting structure to reduce dimensionality and perform efficient parameter extraction, current ADCs do not exploit such knowledge.
We challenge current practice that separates the sampling stage from the processing stage and exploit structure in analog signals already in the ADC, to drastically reduce the sampling and processing rates.
Our preliminary data shows that this allows substantial savings in sampling and processing rates --- we show rate reduction of 1/28 in ultrasound imaging, and 1/30 in radar detection.
To achieve our overreaching goal we focus on three interconnected objectives -- developing the 1) theory 2) hardware and 3) applications of sub-Nyquist sampling.
Our methodology ties together two areas on the frontier of signal processing: compressed sensing (CS), focused on finite length vectors, and analog sampling. Our research plan also inherently relies on advances in several other important areas within signal processing and combines multi-disciplinary research at the intersection of signal processing, information theory, optimization, estimation theory and hardware design.
Max ERC Funding
2 400 000 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym BRAINPLASTICITY
Project In vivo imaging of functional plasticity in the mammalian brain
Researcher (PI) Adi Mizrahi
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary "The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."
Summary
"The dynamic nature of the brain operates at disparate time scales ranging from milliseconds to months. How do single neurons change over such long time scales? This question remains stubborn to answer in the field of brain plasticity mainly because of limited tools to study the physiology of single neurons over time in the complex environment of the brain. The research aim of this proposal is to reveal the physiological changes of single neurons in the mammalian brain over disparate time scales using time-lapse optical imaging. Specifically, we aim to establish a new team that will develop genetic and optical tools to probe the physiological activity of single neurons, in vivo. As a model system, we will study a unique neuronal population in the mammalian brain; the adult-born local neurons in the olfactory bulb. These neurons have tremendous potential to reveal how neurons develop and maintain in the intact brain because they are accessible both genetically and optically. By following the behavior of adult-born neurons in vivo we will discover how neurons mature and maintain over days and weeks. If our objectives will be met, this study has the potential to significantly ""raise the bar"" on how neuronal plasticity is studied and reveal some basic secrets of the ever changing mammalian brain."
Max ERC Funding
1 750 000 €
Duration
Start date: 2008-08-01, End date: 2013-07-31
Project acronym CaNANObinoids
Project From Peripheralized to Cell- and Organelle-Targeted Medicine: The 3rd Generation of Cannabinoid-1 Receptor Antagonists for the Treatment of Chronic Kidney Disease
Researcher (PI) Yossef Tam
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2015-STG
Summary Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited.
The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands.
The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.
Summary
Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited.
The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands.
The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
