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 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
Project acronym CardHeal
Project Novel strategies for mammalian cardiac repair
Researcher (PI) Eldad TZAHOR
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Recent ground-breaking studies by my team and others demonstrated that latent heart regeneration machinery can be awakened even in adult mammals. My lab’s main contribution is the identification of two, apparently different, molecular mechanisms for augmenting cardiac regeneration in adult mice. The first requires transient activation of ErbB2 signalling in cardiomyocytes and the second involves extra cellular matrix-driven signalling by the proteoglycan agrin. Impressively, both mechanisms promote a major regenerative response that, in turn, enhances cardiac repair. In CardHeal we will use the two powerful regenerative models to obtain a holistic view of cardiac regeneration and repair mechanisms in mammals (mice and pigs).
In Aim 1, we will explore the molecular mechanisms underlying our discovery that transient activation of ErbB2 in adult cardiomyocytes results in massive cardiomyocyte dedifferentiation and proliferation followed by new vessels formation, scar resolution and functional cardiac repair. Specific objectives focus on ErbB2-Yap/Hippo signalling during cardiac regeneration; ErbB2 activation in a chronic heart failure model; ErbB2-induced regenerative EMT-like process; and cardiomyocyte re-differentiation.
In Aim 2, we will investigate the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives are matrix-related cardiac regenerative cues, modulation of the immune response, angiogenesis, matrix remodeling, and developing a preclinical, large animal model to study agrin efficacy for cardiac repair.
Interrogating the differences and similarities between our two regenerative models should give us a detailed roadmap for cardiac regenerative medicine by providing deeper knowledge of the regenerative process in the heart and pointing to novel targets for cardiac repair in human patients.
Summary
Recent ground-breaking studies by my team and others demonstrated that latent heart regeneration machinery can be awakened even in adult mammals. My lab’s main contribution is the identification of two, apparently different, molecular mechanisms for augmenting cardiac regeneration in adult mice. The first requires transient activation of ErbB2 signalling in cardiomyocytes and the second involves extra cellular matrix-driven signalling by the proteoglycan agrin. Impressively, both mechanisms promote a major regenerative response that, in turn, enhances cardiac repair. In CardHeal we will use the two powerful regenerative models to obtain a holistic view of cardiac regeneration and repair mechanisms in mammals (mice and pigs).
In Aim 1, we will explore the molecular mechanisms underlying our discovery that transient activation of ErbB2 in adult cardiomyocytes results in massive cardiomyocyte dedifferentiation and proliferation followed by new vessels formation, scar resolution and functional cardiac repair. Specific objectives focus on ErbB2-Yap/Hippo signalling during cardiac regeneration; ErbB2 activation in a chronic heart failure model; ErbB2-induced regenerative EMT-like process; and cardiomyocyte re-differentiation.
In Aim 2, we will investigate the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives are matrix-related cardiac regenerative cues, modulation of the immune response, angiogenesis, matrix remodeling, and developing a preclinical, large animal model to study agrin efficacy for cardiac repair.
Interrogating the differences and similarities between our two regenerative models should give us a detailed roadmap for cardiac regenerative medicine by providing deeper knowledge of the regenerative process in the heart and pointing to novel targets for cardiac repair in human patients.
Max ERC Funding
2 268 750 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CARDIO-IPS
Project Induced Pluripotent stem Cells: A Novel Strategy to Study Inherited Cardiac Disorders
Researcher (PI) Lior Gepstein
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary The study of several genetic disorders is hampered by the lack of suitable in vitro human models. We hypothesize that the generation of patient-specific induced pluripotent stem cells (iPSCs) will allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. In the current proposal we plan utilize this novel approach to establish human iPSC (hiPSC) lines for the study of a variety of inherited cardiac disorders. The specific disease states that will be studied were chosen to reflect abnormalities in a wide-array of different cardiomyocyte cellular processes.
These include mutations leading to:
(1) abnormal ion channel function (“channelopathies”), such as the long QT and Brugada syndromes;
(2) abnormal intracellular storage of unnecessary material, such as in the glycogen storage disease type IIb (Pompe’s disease); and
(3) abnormalities in cell-to-cell contacts, such as in the case of arrhythmogenic right ventricular cardiomyopathy-dysplasia (ARVC-D). The different hiPSC lines generated will be coaxed to differentiate into the cardiac lineage. Detailed molecular, structural, functional, and pharmacological studies will then be performed to characterize the phenotypic properties of the generated hiPSC-derived cardiomyocytes, with specific emphasis on their molecular, ultrastructural, electrophysiological, and Ca2+ handling properties.
These studies should provide new insights into the pathophysiological mechanisms underlying the different familial arrhythmogenic and cardiomyopathy disorders studied, may allow optimization of patient-specific therapies (personalized medicine), and may facilitate the development of novel therapeutic strategies.
Moreover, the concepts and methodological knowhow developed in the current project could be extended, in the future, to derive human disease-specific cell culture models for a plurality of genetic disorders; enabling translational research ranging from investigation of the most fundamental cellular mechanisms involved in human tissue formation and physiology through disease investigation and the development and testing of novel therapies that could potentially find their way to the bedside
Summary
The study of several genetic disorders is hampered by the lack of suitable in vitro human models. We hypothesize that the generation of patient-specific induced pluripotent stem cells (iPSCs) will allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. In the current proposal we plan utilize this novel approach to establish human iPSC (hiPSC) lines for the study of a variety of inherited cardiac disorders. The specific disease states that will be studied were chosen to reflect abnormalities in a wide-array of different cardiomyocyte cellular processes.
These include mutations leading to:
(1) abnormal ion channel function (“channelopathies”), such as the long QT and Brugada syndromes;
(2) abnormal intracellular storage of unnecessary material, such as in the glycogen storage disease type IIb (Pompe’s disease); and
(3) abnormalities in cell-to-cell contacts, such as in the case of arrhythmogenic right ventricular cardiomyopathy-dysplasia (ARVC-D). The different hiPSC lines generated will be coaxed to differentiate into the cardiac lineage. Detailed molecular, structural, functional, and pharmacological studies will then be performed to characterize the phenotypic properties of the generated hiPSC-derived cardiomyocytes, with specific emphasis on their molecular, ultrastructural, electrophysiological, and Ca2+ handling properties.
These studies should provide new insights into the pathophysiological mechanisms underlying the different familial arrhythmogenic and cardiomyopathy disorders studied, may allow optimization of patient-specific therapies (personalized medicine), and may facilitate the development of novel therapeutic strategies.
Moreover, the concepts and methodological knowhow developed in the current project could be extended, in the future, to derive human disease-specific cell culture models for a plurality of genetic disorders; enabling translational research ranging from investigation of the most fundamental cellular mechanisms involved in human tissue formation and physiology through disease investigation and the development and testing of novel therapies that could potentially find their way to the bedside
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-03-01, End date: 2016-02-29
Project acronym CM TURNOVER
Project Uncovering the Mechanisms of Cardiomyocyte Differentiation and Dedifferentiation
Researcher (PI) Eldad Tzahor
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary The quest to restore damaged organs is one of the major challenges in medicine. Recent studies in both animals and in humans suggest that the heart has a limited capacity to replenish its own cardiomyocytes (CMs) throughout life, albeit inadequate to compensate for major injuries such as acute myocardial infarction (MI). Most therapeutic research in regenerative cardiogenesis is geared toward stem cell therapy as a means to replace lost CMs associated with ischemic heart disease. Clinical data evaluating the efficacy of cell-based therapy for heart disease are relatively disappointing. This proposal encompasses multidisciplinary and novel approaches to study the molecular and cellular mechanisms that govern the proliferation, differentiation and dedifferentiation of endogenous CMs, combining developmental-, systems- and cell-biology methodologies in vitro and in vivo, in chick, rodent, and human tissue samples. First, we will perform combinatorial perturbations of signaling pathways in chick embryos, focusing primarily on the FGF-ERK pathway, to investigate the molecular switch between cardiac progenitors and CMs (Aim 1). Because adult CMs have limited proliferative capacity, mainly due to mechanical constraints, in Aim 2, we will apply state-of-the-art techniques in cell biology, to determine whether specific mechno-transduction stimuli can prime the proliferation of differentiated CMs. In order to gain deeper insights into the capacity of adult CMs to renew themselves under normal and pathological conditions, in Aim 3, we will employ a novel cell lineage methodology in mouse and human tissue, based on information encoded in genome. Using this methodology, we hope to shed light on the maintenance, renewal and regenerative capacities of adult CMs in vivo. The expected outcome will be a significantly greater understanding of the bidirectional transition from proliferating cardiac progenitors into differentiated CMs, in embryonic and adult hearts.
Summary
The quest to restore damaged organs is one of the major challenges in medicine. Recent studies in both animals and in humans suggest that the heart has a limited capacity to replenish its own cardiomyocytes (CMs) throughout life, albeit inadequate to compensate for major injuries such as acute myocardial infarction (MI). Most therapeutic research in regenerative cardiogenesis is geared toward stem cell therapy as a means to replace lost CMs associated with ischemic heart disease. Clinical data evaluating the efficacy of cell-based therapy for heart disease are relatively disappointing. This proposal encompasses multidisciplinary and novel approaches to study the molecular and cellular mechanisms that govern the proliferation, differentiation and dedifferentiation of endogenous CMs, combining developmental-, systems- and cell-biology methodologies in vitro and in vivo, in chick, rodent, and human tissue samples. First, we will perform combinatorial perturbations of signaling pathways in chick embryos, focusing primarily on the FGF-ERK pathway, to investigate the molecular switch between cardiac progenitors and CMs (Aim 1). Because adult CMs have limited proliferative capacity, mainly due to mechanical constraints, in Aim 2, we will apply state-of-the-art techniques in cell biology, to determine whether specific mechno-transduction stimuli can prime the proliferation of differentiated CMs. In order to gain deeper insights into the capacity of adult CMs to renew themselves under normal and pathological conditions, in Aim 3, we will employ a novel cell lineage methodology in mouse and human tissue, based on information encoded in genome. Using this methodology, we hope to shed light on the maintenance, renewal and regenerative capacities of adult CMs in vivo. The expected outcome will be a significantly greater understanding of the bidirectional transition from proliferating cardiac progenitors into differentiated CMs, in embryonic and adult hearts.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym cureCD
Project Function of long non-coding RNA in Crohn Disease Ulcer Pathogenesis
Researcher (PI) Yael HABERMAN ZIV
Host Institution (HI) MEDICAL RESEARCH INFRASTRUCTURE DEVELOPMENT AND HEALTH SERVICES FUND BY THE SHEBA MEDICAL CENTER
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes.
Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota.
I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.
Summary
The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes.
Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota.
I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym ELIMINATESENESCENT
Project The Role of Elimination of Senescent Cells in Cancer Development
Researcher (PI) Valery Krizhanovsky
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.
Summary
Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells.
The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells.
The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym iPS-ChOp-AF
Project Combining induced pluripotent stem cells, tissue engineering, optogenetic and chemogenetic concepts for the study and treatment of atrial fibrillation
Researcher (PI) Lior GEPSTEIN
Host Institution (HI) TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary "Cardiac arrhythmias are responsible for significant morbidity and mortality. However, the study and treatment of these rhythm disorders have been hampered by the lack of relevant human cardiac tissue models, specifically those reflecting patient/disease-specific abnormalities, by paucity of methods for long-term electrophysiological analysis of the tissue, and by the inability to perform targeted, high-resolution, reversible, and functional perturbations of the system.
To address these challenges, we propose to combine human induced pluripotent stem cells (hiPSC) and genome-editing (CRISPR) technologies, developmental biology-inspired differentiating systems that yield chamber-specific heart cells, novel tissue engineering strategies, and emerging concepts from the fields of optogenetics and chemogenetics. The resulting experimental models should represent a paradigm shift in the way we study and treat cardiac arrhythmias. To demonstrate the unique potential of this approach, we plan to focus on atrial fibrillation (AF), the most common arrhythmia.
Our specific aims are to:
1. Develop patient/disease-specific hiPSC models of genetic AF and to establish hiPSC differentiation protocols to yield purified atrial cells
2. Utilize the hiPSC-atrial cells and advanced tissue-engineering strategies (hydrogels, 3D printing, decellularization) to establish 2D cell-sheet and 3D tissue models of acquired and inherited AF, in which functional re-entry (""rotors"") can be studied
3. Utilize tools from optogenetics (light-sensitive ion channels and pumps) or chemogenetics (ligand-specific engineered receptors) for targeted manipulation of the system, to gain insights into AF pathogenesis and to develop novel therapies
4. Evaluate the developed optogenetic and chemogenetic treatments in animal models of AF
The results of this project should provide novel mechanistic insights into AF (and other arrhythmias) and open the road for the development of novel therapeutic paradigms."
Summary
"Cardiac arrhythmias are responsible for significant morbidity and mortality. However, the study and treatment of these rhythm disorders have been hampered by the lack of relevant human cardiac tissue models, specifically those reflecting patient/disease-specific abnormalities, by paucity of methods for long-term electrophysiological analysis of the tissue, and by the inability to perform targeted, high-resolution, reversible, and functional perturbations of the system.
To address these challenges, we propose to combine human induced pluripotent stem cells (hiPSC) and genome-editing (CRISPR) technologies, developmental biology-inspired differentiating systems that yield chamber-specific heart cells, novel tissue engineering strategies, and emerging concepts from the fields of optogenetics and chemogenetics. The resulting experimental models should represent a paradigm shift in the way we study and treat cardiac arrhythmias. To demonstrate the unique potential of this approach, we plan to focus on atrial fibrillation (AF), the most common arrhythmia.
Our specific aims are to:
1. Develop patient/disease-specific hiPSC models of genetic AF and to establish hiPSC differentiation protocols to yield purified atrial cells
2. Utilize the hiPSC-atrial cells and advanced tissue-engineering strategies (hydrogels, 3D printing, decellularization) to establish 2D cell-sheet and 3D tissue models of acquired and inherited AF, in which functional re-entry (""rotors"") can be studied
3. Utilize tools from optogenetics (light-sensitive ion channels and pumps) or chemogenetics (ligand-specific engineered receptors) for targeted manipulation of the system, to gain insights into AF pathogenesis and to develop novel therapies
4. Evaluate the developed optogenetic and chemogenetic treatments in animal models of AF
The results of this project should provide novel mechanistic insights into AF (and other arrhythmias) and open the road for the development of novel therapeutic paradigms."
Max ERC Funding
1 988 750 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
