Biochemistry (Pieters)Head of Research Unit Prof. Dr.Jean PietersOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 47 foundShow per page10 10 20 50 Coronin 1 and the control of T cell population size Research Project | 1 Project MembersImported from Grants Tool 4701413 Targeting the Coronin Signaling Pathway Research Project | 1 Project MembersImported from Grants Tool 4702359 Targeting the Coronin Signaling Pathway for the Treatment of Leukemia Research Project | 1 Project MembersNo Description available InnoBooster - Nextimmune Research Project | 3 Project MembersWe have identified a novel therapeutic approach for the treatment of autoimmune-inflammatory diseases and organ transplantation. Under this granted project, we aim to improve the therapeutic potential of the research concept for further preclinical development. Analysis of the role of the coronin 1 signalling pathway in glioblastoma through a systems medicine approach Research Project | 1 Project MembersGlioblastoma is the most common, highly aggressive, malignant primary brain tumour with one of the worst prognoses among aggressive cancers. Despite the development of advanced multimodal therapeutic strategies, which combine aggressive surgery, radiation, and chemotherapy, patients with glioblastoma have a dismal prognosis, with a median overall survival time of less than 18 months from the time of diagnosis. One of the main problems is that glioblastoma is a highly complex disease, with a poor understanding of the key drivers of tumorigenesis1. As a result, no specific treatment for glioblastoma is available, and patients are currently treated with a combination of surgery, radiation and chemotherapy in an attempt to non-selectively dampen cell growth. While specific molecular drivers remain largely unknown, it is believed that glioblastoma occurs as a result of modulation of diverse neuro-glioma signalling pathways and a capacity to suppress immune destruction to drive proliferation and invasion. In particular, glioblastoma is associated with a reduction of the second messenger cAMP in glioma cells and induction of T cell-mediated immunosuppression, both of which are key drivers of glioma tumour cell growth. One pathway that has recently emerged to play a key role in cell proliferation, neuronal signalling and cAMP-dependent T cell-mediated immunosuppression is the coronin 1 signalling pathway. Coronin 1 is expressed in excitatory neurons, glial cells and T cells; strikingly, preliminary data suggest highly significant downregulation of coronin 1 in biopsies from glioblastoma patients. The goal of the current research proposal is to use a systems medicine approach to dissect and analyse a role for deregulated coronin 1 signalling in glioblastoma. In particular, we will use patient-derived cells and tissues from patient cohorts, cell lines, orthotopic and xenograft mouse models to (i) analyse coronin 1-dependent glioma proliferation, migration and invasion in vitro and in vivo; (ii) analyse coronin 1-dependent (neuro) gliomal synaptic signalling; (iii) perform system-based analysis to dissect neuro-glioblastoma signalling using patient-derived xenograft murine models through the application of (phospho-) proteomics and transcriptomics; (iv) assess coronin 1-dependent immunosuppression in biopsy-isolated T cells. The coronin 1 pathway has recently emerged as an important regulator of such diverse pathways as cell proliferation, neuronal signalling and immunosuppression. However, there is no knowledge on any role for this pathway in glioblastoma. Given the high risk/high gain nature of the proposed work, we believe that the combined expertise of the applicants' laboratories together with the innovative and systems-based approaches proposed in this grant may allow the definition of hitherto unknown mechanisms driving glioblastoma. Furthermore, knowledge on the precise molecular pathways involved in glioblastoma may not only unravel the complexity of glioblastoma, but also allow specific targeting of such pathways, including methods to overcome suppression of antitumor responses, in order to foster development of innovative diagnostic, prognostic and therapeutic approaches. Coronin-1 Inhibitors as a revolutionary therapy for the prevention of transplant rejection Research Project | 1 Project MembersNo Description available Investigating the role for coronin 1 in T cell homeostasis and immune tolerance Research Project | 3 Project MembersCells within tissues and organs need to maintain homeostatic numbers to function properly. While in many tissues this is achieved through heterotypic cell-to-cell interaction and/or the sensing of growth factor gradients, for individually circulating cells such as T cells, that are known to populate their space at near-constant numbers, it is unknown what determines their exact population size. In addition, dysregulation of T cell homeostasis is associated with autoimmune diseases, pathological reactions against transplanted organs, and cancers.Whereas thus far, T cell homeostasis has been attributed to T cell receptor (TCR) signaling through Major Histocompatibility Complex (MHC)-self peptides and/or interleukin-7 (IL-7) signaling, recent work from our laboratory suggests the existence of a third pathway that is independent of TCR/interleukin-7, and is instead regulated by coronin 1. Coronin 1 is a member of the evolutionary conserved Tryptophan-Aspartate (WD) repeat protein family of coronins, that are widely expressed in all eukaryotic organisms. Although the molecular function of coronin molecules has been linked to a role in F-actin rearrangement, more recent work suggests that coronin 1 regulates T cell homeostasis in an F-actin-independent manner, but the mechanisms via which coronin 1 does so remain unknown. In the previous granting period we have uncovered a role for coronin 1 in the regulation of cyclic Adenosine Mono Phosphate (cAMP)-dependent signal transduction in T cells. Notably, we found that coronin 1 deletion results in the establishment of a cAMP-dependent immunosuppressive environment thereby dampening auto- and alloimmune responses. Importantly, we found that disruption of coronin 1 signaling in T cells promotes allograft tolerance while maintaining anti-pathogen immunity. In work that is currently being prepared for submission, we show that this pathway can be targeted to prevent autoimmunity, and we therefore believe that we have been able to significantly contribute novel insight towards an important problem. In the next granting period, we aim to address 2 main aims. First, we aim to delineate the molecular mechanism underlying coronin 1-dependent T cell homeostasis, through (i) analyzing the signal transduction cascade(s) in which coronin 1 is involved; (ii) defining the coronin 1 interactome in T cells and (iii) unraveling the regulatory network involved in coronin 1 transcription. Second, we aim to understand the induction of selective immunosuppression induced by coronin 1 deletion. This will be achieved by analyzing the mechanism of immunosuppression upon coronin 1 deletion as well as dissect the molecular pathways involved in allo- and auto-immune responses versus anti-pathogen responses. These aims will be addressed using a combination of state-of-the-art biochemical, molecular and cell biological techniques, including siRNA- and CRISPR/Cas9-based screening, total transcriptome analysis and mass spectrometry as well as stem cell-based reconstitution of T cell homeostasis in animal models. We believe that this work will allow to define a hitherto unknown signal transduction pathway regulating T cell homeostasis as well as contribute to the further characterization of an entirely novel and targetable pathway selectively involved in allo-and autoimmune responses. Finally, given the observed parallels between the role for coronin 1 in T cell homeostasis and coronin A's role in the regulation of growth and multicellular development in the lower eukaryote Dictyostelium discoideum, the work proposed here may allow to unravel a hitherto uncharacterized signaling pathway involved in cellular homeostasis conserved from amoeba to humans. Development of compounds for the induction of tolerance following heart transplantation Research Project | 1 Project MembersHeart failure is a life-threatening disease, with an estimated 25 million people being currently affected worldwide. While many factors can contribute to heart failure, one of the best treatment options for many of these would be transplantation of a healthy heart. Unfortunately, other than in the case of an identical twin, all donor hearts suffer from mismatching, resulting in high rejection rates. Moreover, even after receiving an appropriately-matched donor heart, recipients often require life-long immunosuppression. This makes them highly susceptible to opportunistic infections and spontaneous cancers. A therapy allowing mismatched heart transplantations without the need for overt immunosuppression is currently not available. Graft rejection following transplantation is mainly caused by activation of a subset of immune cells, called T cells. These cells recognize a donor organ as foreign, and therefore initiate an immune response against the graft, thereby effectively rejecting the transplanted organ. We have recently identified a hitherto unknown T cell-dependent pathway that mediates suppression of rejection following heart transplantation involving an immune cell-specific protein termed coronin 1. In recently published work (Immunity, 2019), we found that coronin 1 deletion resulted in long-term acceptance of mismatched heart allografts, in the absence of any other immunosuppressive therapy. The goal of the proposed project is to develop inhibitors of the coronin 1-dependent pathway, that may be useful for the prevention of rejection following heart allo-transplantation. The results from this project may allow the introduction of a therapy that has first of all the potential to increase the donor base by allowing heart allo-transplantation to occur between HLA-mismatched individuals. Secondly, it will allow the treatment of end-stage heart failure patients having undergone allotransplantation to avoid graft rejection. Such therapy may overcome the problems associated with overt immunosuppression including susceptibility towards infections, graft versus host disease and the development of tumors associated with conventional immunosuppression. Together the research may result in novel treatment options for patients suffering from end-stage heart disease. Analysis of Substrate Phosphorylation by a Virulence Factor from Mycobacterium tuberculosis to Modulate of Host Defence Responses Research Project | 1 Project MembersMycobacterium tuberculosis, one of the most notorious pathogens on earth, has evolved to evade host immunodetection at multiple levels. The applicants of the scientific exchange proposal have obtained preliminary evidence that a well-known virulence factor produced by M. tuberculosis, the serine/threonine kinase protein kinase G (PknG), modu;lates macrophage biology through its kinase activity. The goal of the scientific exchange is to thoroughly characterize the events associated with this mechanism. This work will on the one hand help to uncover a hitherto unknown virulence mechanism employed by M. tuberculosis, and on the other hand further strengthen the existing collaboration between our laboratories. Analysis of the coronin 1 interactome by quantitative proteomics Research Project | 1 Project MembersAnalysis of the coronin 1 interactome by quantitative proteomics. 12345 1...5 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 47 foundShow per page10 10 20 50 Coronin 1 and the control of T cell population size Research Project | 1 Project MembersImported from Grants Tool 4701413 Targeting the Coronin Signaling Pathway Research Project | 1 Project MembersImported from Grants Tool 4702359 Targeting the Coronin Signaling Pathway for the Treatment of Leukemia Research Project | 1 Project MembersNo Description available InnoBooster - Nextimmune Research Project | 3 Project MembersWe have identified a novel therapeutic approach for the treatment of autoimmune-inflammatory diseases and organ transplantation. Under this granted project, we aim to improve the therapeutic potential of the research concept for further preclinical development. Analysis of the role of the coronin 1 signalling pathway in glioblastoma through a systems medicine approach Research Project | 1 Project MembersGlioblastoma is the most common, highly aggressive, malignant primary brain tumour with one of the worst prognoses among aggressive cancers. Despite the development of advanced multimodal therapeutic strategies, which combine aggressive surgery, radiation, and chemotherapy, patients with glioblastoma have a dismal prognosis, with a median overall survival time of less than 18 months from the time of diagnosis. One of the main problems is that glioblastoma is a highly complex disease, with a poor understanding of the key drivers of tumorigenesis1. As a result, no specific treatment for glioblastoma is available, and patients are currently treated with a combination of surgery, radiation and chemotherapy in an attempt to non-selectively dampen cell growth. While specific molecular drivers remain largely unknown, it is believed that glioblastoma occurs as a result of modulation of diverse neuro-glioma signalling pathways and a capacity to suppress immune destruction to drive proliferation and invasion. In particular, glioblastoma is associated with a reduction of the second messenger cAMP in glioma cells and induction of T cell-mediated immunosuppression, both of which are key drivers of glioma tumour cell growth. One pathway that has recently emerged to play a key role in cell proliferation, neuronal signalling and cAMP-dependent T cell-mediated immunosuppression is the coronin 1 signalling pathway. Coronin 1 is expressed in excitatory neurons, glial cells and T cells; strikingly, preliminary data suggest highly significant downregulation of coronin 1 in biopsies from glioblastoma patients. The goal of the current research proposal is to use a systems medicine approach to dissect and analyse a role for deregulated coronin 1 signalling in glioblastoma. In particular, we will use patient-derived cells and tissues from patient cohorts, cell lines, orthotopic and xenograft mouse models to (i) analyse coronin 1-dependent glioma proliferation, migration and invasion in vitro and in vivo; (ii) analyse coronin 1-dependent (neuro) gliomal synaptic signalling; (iii) perform system-based analysis to dissect neuro-glioblastoma signalling using patient-derived xenograft murine models through the application of (phospho-) proteomics and transcriptomics; (iv) assess coronin 1-dependent immunosuppression in biopsy-isolated T cells. The coronin 1 pathway has recently emerged as an important regulator of such diverse pathways as cell proliferation, neuronal signalling and immunosuppression. However, there is no knowledge on any role for this pathway in glioblastoma. Given the high risk/high gain nature of the proposed work, we believe that the combined expertise of the applicants' laboratories together with the innovative and systems-based approaches proposed in this grant may allow the definition of hitherto unknown mechanisms driving glioblastoma. Furthermore, knowledge on the precise molecular pathways involved in glioblastoma may not only unravel the complexity of glioblastoma, but also allow specific targeting of such pathways, including methods to overcome suppression of antitumor responses, in order to foster development of innovative diagnostic, prognostic and therapeutic approaches. Coronin-1 Inhibitors as a revolutionary therapy for the prevention of transplant rejection Research Project | 1 Project MembersNo Description available Investigating the role for coronin 1 in T cell homeostasis and immune tolerance Research Project | 3 Project MembersCells within tissues and organs need to maintain homeostatic numbers to function properly. While in many tissues this is achieved through heterotypic cell-to-cell interaction and/or the sensing of growth factor gradients, for individually circulating cells such as T cells, that are known to populate their space at near-constant numbers, it is unknown what determines their exact population size. In addition, dysregulation of T cell homeostasis is associated with autoimmune diseases, pathological reactions against transplanted organs, and cancers.Whereas thus far, T cell homeostasis has been attributed to T cell receptor (TCR) signaling through Major Histocompatibility Complex (MHC)-self peptides and/or interleukin-7 (IL-7) signaling, recent work from our laboratory suggests the existence of a third pathway that is independent of TCR/interleukin-7, and is instead regulated by coronin 1. Coronin 1 is a member of the evolutionary conserved Tryptophan-Aspartate (WD) repeat protein family of coronins, that are widely expressed in all eukaryotic organisms. Although the molecular function of coronin molecules has been linked to a role in F-actin rearrangement, more recent work suggests that coronin 1 regulates T cell homeostasis in an F-actin-independent manner, but the mechanisms via which coronin 1 does so remain unknown. In the previous granting period we have uncovered a role for coronin 1 in the regulation of cyclic Adenosine Mono Phosphate (cAMP)-dependent signal transduction in T cells. Notably, we found that coronin 1 deletion results in the establishment of a cAMP-dependent immunosuppressive environment thereby dampening auto- and alloimmune responses. Importantly, we found that disruption of coronin 1 signaling in T cells promotes allograft tolerance while maintaining anti-pathogen immunity. In work that is currently being prepared for submission, we show that this pathway can be targeted to prevent autoimmunity, and we therefore believe that we have been able to significantly contribute novel insight towards an important problem. In the next granting period, we aim to address 2 main aims. First, we aim to delineate the molecular mechanism underlying coronin 1-dependent T cell homeostasis, through (i) analyzing the signal transduction cascade(s) in which coronin 1 is involved; (ii) defining the coronin 1 interactome in T cells and (iii) unraveling the regulatory network involved in coronin 1 transcription. Second, we aim to understand the induction of selective immunosuppression induced by coronin 1 deletion. This will be achieved by analyzing the mechanism of immunosuppression upon coronin 1 deletion as well as dissect the molecular pathways involved in allo- and auto-immune responses versus anti-pathogen responses. These aims will be addressed using a combination of state-of-the-art biochemical, molecular and cell biological techniques, including siRNA- and CRISPR/Cas9-based screening, total transcriptome analysis and mass spectrometry as well as stem cell-based reconstitution of T cell homeostasis in animal models. We believe that this work will allow to define a hitherto unknown signal transduction pathway regulating T cell homeostasis as well as contribute to the further characterization of an entirely novel and targetable pathway selectively involved in allo-and autoimmune responses. Finally, given the observed parallels between the role for coronin 1 in T cell homeostasis and coronin A's role in the regulation of growth and multicellular development in the lower eukaryote Dictyostelium discoideum, the work proposed here may allow to unravel a hitherto uncharacterized signaling pathway involved in cellular homeostasis conserved from amoeba to humans. Development of compounds for the induction of tolerance following heart transplantation Research Project | 1 Project MembersHeart failure is a life-threatening disease, with an estimated 25 million people being currently affected worldwide. While many factors can contribute to heart failure, one of the best treatment options for many of these would be transplantation of a healthy heart. Unfortunately, other than in the case of an identical twin, all donor hearts suffer from mismatching, resulting in high rejection rates. Moreover, even after receiving an appropriately-matched donor heart, recipients often require life-long immunosuppression. This makes them highly susceptible to opportunistic infections and spontaneous cancers. A therapy allowing mismatched heart transplantations without the need for overt immunosuppression is currently not available. Graft rejection following transplantation is mainly caused by activation of a subset of immune cells, called T cells. These cells recognize a donor organ as foreign, and therefore initiate an immune response against the graft, thereby effectively rejecting the transplanted organ. We have recently identified a hitherto unknown T cell-dependent pathway that mediates suppression of rejection following heart transplantation involving an immune cell-specific protein termed coronin 1. In recently published work (Immunity, 2019), we found that coronin 1 deletion resulted in long-term acceptance of mismatched heart allografts, in the absence of any other immunosuppressive therapy. The goal of the proposed project is to develop inhibitors of the coronin 1-dependent pathway, that may be useful for the prevention of rejection following heart allo-transplantation. The results from this project may allow the introduction of a therapy that has first of all the potential to increase the donor base by allowing heart allo-transplantation to occur between HLA-mismatched individuals. Secondly, it will allow the treatment of end-stage heart failure patients having undergone allotransplantation to avoid graft rejection. Such therapy may overcome the problems associated with overt immunosuppression including susceptibility towards infections, graft versus host disease and the development of tumors associated with conventional immunosuppression. Together the research may result in novel treatment options for patients suffering from end-stage heart disease. Analysis of Substrate Phosphorylation by a Virulence Factor from Mycobacterium tuberculosis to Modulate of Host Defence Responses Research Project | 1 Project MembersMycobacterium tuberculosis, one of the most notorious pathogens on earth, has evolved to evade host immunodetection at multiple levels. The applicants of the scientific exchange proposal have obtained preliminary evidence that a well-known virulence factor produced by M. tuberculosis, the serine/threonine kinase protein kinase G (PknG), modu;lates macrophage biology through its kinase activity. The goal of the scientific exchange is to thoroughly characterize the events associated with this mechanism. This work will on the one hand help to uncover a hitherto unknown virulence mechanism employed by M. tuberculosis, and on the other hand further strengthen the existing collaboration between our laboratories. Analysis of the coronin 1 interactome by quantitative proteomics Research Project | 1 Project MembersAnalysis of the coronin 1 interactome by quantitative proteomics. 12345 1...5
Coronin 1 and the control of T cell population size Research Project | 1 Project MembersImported from Grants Tool 4701413
Targeting the Coronin Signaling Pathway Research Project | 1 Project MembersImported from Grants Tool 4702359
Targeting the Coronin Signaling Pathway for the Treatment of Leukemia Research Project | 1 Project MembersNo Description available
InnoBooster - Nextimmune Research Project | 3 Project MembersWe have identified a novel therapeutic approach for the treatment of autoimmune-inflammatory diseases and organ transplantation. Under this granted project, we aim to improve the therapeutic potential of the research concept for further preclinical development.
Analysis of the role of the coronin 1 signalling pathway in glioblastoma through a systems medicine approach Research Project | 1 Project MembersGlioblastoma is the most common, highly aggressive, malignant primary brain tumour with one of the worst prognoses among aggressive cancers. Despite the development of advanced multimodal therapeutic strategies, which combine aggressive surgery, radiation, and chemotherapy, patients with glioblastoma have a dismal prognosis, with a median overall survival time of less than 18 months from the time of diagnosis. One of the main problems is that glioblastoma is a highly complex disease, with a poor understanding of the key drivers of tumorigenesis1. As a result, no specific treatment for glioblastoma is available, and patients are currently treated with a combination of surgery, radiation and chemotherapy in an attempt to non-selectively dampen cell growth. While specific molecular drivers remain largely unknown, it is believed that glioblastoma occurs as a result of modulation of diverse neuro-glioma signalling pathways and a capacity to suppress immune destruction to drive proliferation and invasion. In particular, glioblastoma is associated with a reduction of the second messenger cAMP in glioma cells and induction of T cell-mediated immunosuppression, both of which are key drivers of glioma tumour cell growth. One pathway that has recently emerged to play a key role in cell proliferation, neuronal signalling and cAMP-dependent T cell-mediated immunosuppression is the coronin 1 signalling pathway. Coronin 1 is expressed in excitatory neurons, glial cells and T cells; strikingly, preliminary data suggest highly significant downregulation of coronin 1 in biopsies from glioblastoma patients. The goal of the current research proposal is to use a systems medicine approach to dissect and analyse a role for deregulated coronin 1 signalling in glioblastoma. In particular, we will use patient-derived cells and tissues from patient cohorts, cell lines, orthotopic and xenograft mouse models to (i) analyse coronin 1-dependent glioma proliferation, migration and invasion in vitro and in vivo; (ii) analyse coronin 1-dependent (neuro) gliomal synaptic signalling; (iii) perform system-based analysis to dissect neuro-glioblastoma signalling using patient-derived xenograft murine models through the application of (phospho-) proteomics and transcriptomics; (iv) assess coronin 1-dependent immunosuppression in biopsy-isolated T cells. The coronin 1 pathway has recently emerged as an important regulator of such diverse pathways as cell proliferation, neuronal signalling and immunosuppression. However, there is no knowledge on any role for this pathway in glioblastoma. Given the high risk/high gain nature of the proposed work, we believe that the combined expertise of the applicants' laboratories together with the innovative and systems-based approaches proposed in this grant may allow the definition of hitherto unknown mechanisms driving glioblastoma. Furthermore, knowledge on the precise molecular pathways involved in glioblastoma may not only unravel the complexity of glioblastoma, but also allow specific targeting of such pathways, including methods to overcome suppression of antitumor responses, in order to foster development of innovative diagnostic, prognostic and therapeutic approaches.
Coronin-1 Inhibitors as a revolutionary therapy for the prevention of transplant rejection Research Project | 1 Project MembersNo Description available
Investigating the role for coronin 1 in T cell homeostasis and immune tolerance Research Project | 3 Project MembersCells within tissues and organs need to maintain homeostatic numbers to function properly. While in many tissues this is achieved through heterotypic cell-to-cell interaction and/or the sensing of growth factor gradients, for individually circulating cells such as T cells, that are known to populate their space at near-constant numbers, it is unknown what determines their exact population size. In addition, dysregulation of T cell homeostasis is associated with autoimmune diseases, pathological reactions against transplanted organs, and cancers.Whereas thus far, T cell homeostasis has been attributed to T cell receptor (TCR) signaling through Major Histocompatibility Complex (MHC)-self peptides and/or interleukin-7 (IL-7) signaling, recent work from our laboratory suggests the existence of a third pathway that is independent of TCR/interleukin-7, and is instead regulated by coronin 1. Coronin 1 is a member of the evolutionary conserved Tryptophan-Aspartate (WD) repeat protein family of coronins, that are widely expressed in all eukaryotic organisms. Although the molecular function of coronin molecules has been linked to a role in F-actin rearrangement, more recent work suggests that coronin 1 regulates T cell homeostasis in an F-actin-independent manner, but the mechanisms via which coronin 1 does so remain unknown. In the previous granting period we have uncovered a role for coronin 1 in the regulation of cyclic Adenosine Mono Phosphate (cAMP)-dependent signal transduction in T cells. Notably, we found that coronin 1 deletion results in the establishment of a cAMP-dependent immunosuppressive environment thereby dampening auto- and alloimmune responses. Importantly, we found that disruption of coronin 1 signaling in T cells promotes allograft tolerance while maintaining anti-pathogen immunity. In work that is currently being prepared for submission, we show that this pathway can be targeted to prevent autoimmunity, and we therefore believe that we have been able to significantly contribute novel insight towards an important problem. In the next granting period, we aim to address 2 main aims. First, we aim to delineate the molecular mechanism underlying coronin 1-dependent T cell homeostasis, through (i) analyzing the signal transduction cascade(s) in which coronin 1 is involved; (ii) defining the coronin 1 interactome in T cells and (iii) unraveling the regulatory network involved in coronin 1 transcription. Second, we aim to understand the induction of selective immunosuppression induced by coronin 1 deletion. This will be achieved by analyzing the mechanism of immunosuppression upon coronin 1 deletion as well as dissect the molecular pathways involved in allo- and auto-immune responses versus anti-pathogen responses. These aims will be addressed using a combination of state-of-the-art biochemical, molecular and cell biological techniques, including siRNA- and CRISPR/Cas9-based screening, total transcriptome analysis and mass spectrometry as well as stem cell-based reconstitution of T cell homeostasis in animal models. We believe that this work will allow to define a hitherto unknown signal transduction pathway regulating T cell homeostasis as well as contribute to the further characterization of an entirely novel and targetable pathway selectively involved in allo-and autoimmune responses. Finally, given the observed parallels between the role for coronin 1 in T cell homeostasis and coronin A's role in the regulation of growth and multicellular development in the lower eukaryote Dictyostelium discoideum, the work proposed here may allow to unravel a hitherto uncharacterized signaling pathway involved in cellular homeostasis conserved from amoeba to humans.
Development of compounds for the induction of tolerance following heart transplantation Research Project | 1 Project MembersHeart failure is a life-threatening disease, with an estimated 25 million people being currently affected worldwide. While many factors can contribute to heart failure, one of the best treatment options for many of these would be transplantation of a healthy heart. Unfortunately, other than in the case of an identical twin, all donor hearts suffer from mismatching, resulting in high rejection rates. Moreover, even after receiving an appropriately-matched donor heart, recipients often require life-long immunosuppression. This makes them highly susceptible to opportunistic infections and spontaneous cancers. A therapy allowing mismatched heart transplantations without the need for overt immunosuppression is currently not available. Graft rejection following transplantation is mainly caused by activation of a subset of immune cells, called T cells. These cells recognize a donor organ as foreign, and therefore initiate an immune response against the graft, thereby effectively rejecting the transplanted organ. We have recently identified a hitherto unknown T cell-dependent pathway that mediates suppression of rejection following heart transplantation involving an immune cell-specific protein termed coronin 1. In recently published work (Immunity, 2019), we found that coronin 1 deletion resulted in long-term acceptance of mismatched heart allografts, in the absence of any other immunosuppressive therapy. The goal of the proposed project is to develop inhibitors of the coronin 1-dependent pathway, that may be useful for the prevention of rejection following heart allo-transplantation. The results from this project may allow the introduction of a therapy that has first of all the potential to increase the donor base by allowing heart allo-transplantation to occur between HLA-mismatched individuals. Secondly, it will allow the treatment of end-stage heart failure patients having undergone allotransplantation to avoid graft rejection. Such therapy may overcome the problems associated with overt immunosuppression including susceptibility towards infections, graft versus host disease and the development of tumors associated with conventional immunosuppression. Together the research may result in novel treatment options for patients suffering from end-stage heart disease.
Analysis of Substrate Phosphorylation by a Virulence Factor from Mycobacterium tuberculosis to Modulate of Host Defence Responses Research Project | 1 Project MembersMycobacterium tuberculosis, one of the most notorious pathogens on earth, has evolved to evade host immunodetection at multiple levels. The applicants of the scientific exchange proposal have obtained preliminary evidence that a well-known virulence factor produced by M. tuberculosis, the serine/threonine kinase protein kinase G (PknG), modu;lates macrophage biology through its kinase activity. The goal of the scientific exchange is to thoroughly characterize the events associated with this mechanism. This work will on the one hand help to uncover a hitherto unknown virulence mechanism employed by M. tuberculosis, and on the other hand further strengthen the existing collaboration between our laboratories.
Analysis of the coronin 1 interactome by quantitative proteomics Research Project | 1 Project MembersAnalysis of the coronin 1 interactome by quantitative proteomics.
