Project acronym LUPUSCARE
Project PRECISION CARE IN SYSTEMIC AUTOIMMUNITY: AN INTEGRATED MULTI-TISSUE/LEVEL APPROACH FOR SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Researcher (PI) DIMITRIOS BOUMPAS
Host Institution (HI) IDRYMA IATROVIOLOGIKON EREUNON AKADEMIAS ATHINON
Call Details Advanced Grant (AdG), LS7, ERC-2016-ADG
Summary Systemic lupus erythematosus (SLE) is a heterogeneous disease whereby an interplay of environmental, genetic and epigenetic factors lead to perturbation of complex biological networks culminating into diverse clinical phenotypes of varying severity. High throughput methods have allowed an “initial glimpse” into pathogenesis and have laid the foundations for a molecular-based taxonomy for personalized therapy. Based on our experience with the molecular characterization of SLE, a recently completed RNA sequencing analysis of 150 patients, and our track- record of “paradigm shift” trials in SLE, we will integrate data from multi-tissue analyses with novel technologies to improve its diagnosis, monitoring and therapy, and ask fundamental pathogenetic questions in systemic autoimmunity. More specifically, we will design gene expression panels and “expression profile”/”clinical trait” correlation matrices for diagnostics, personalized immunotherapy and improved clinical trial design. In a systematic multi-tissue approach, we will examine the role of somatic mutations in enhancing immune hyperactivity and the risk for lymphoma. The staggering (7-9:1) female predominance will be elucidated through elaborate genomic, epigenomic and microbiota analyses of family trios. Finally, we will be pursuing the innovative hypothesis that the fundamental abnormalities of SLE lie within the bone marrow hematopoietic stem cells (HSCs) - from which all cells that participate in the pathogenesis of SLE originate - and establish it as a unifying pathogenetic mechanism. By a combination of novel experimental analyses with single cell genomics, multi–omics, humanized animal models, genome editing and an “organ on-a-chip” device, we will validate HSCs as a therapeutic target. The utility of SLE research extends beyond its boundaries, by providing unique insights as to how the immune system recognizes self-constituents and maintains its homeostasis, and how gender impacts on disease biology.
Summary
Systemic lupus erythematosus (SLE) is a heterogeneous disease whereby an interplay of environmental, genetic and epigenetic factors lead to perturbation of complex biological networks culminating into diverse clinical phenotypes of varying severity. High throughput methods have allowed an “initial glimpse” into pathogenesis and have laid the foundations for a molecular-based taxonomy for personalized therapy. Based on our experience with the molecular characterization of SLE, a recently completed RNA sequencing analysis of 150 patients, and our track- record of “paradigm shift” trials in SLE, we will integrate data from multi-tissue analyses with novel technologies to improve its diagnosis, monitoring and therapy, and ask fundamental pathogenetic questions in systemic autoimmunity. More specifically, we will design gene expression panels and “expression profile”/”clinical trait” correlation matrices for diagnostics, personalized immunotherapy and improved clinical trial design. In a systematic multi-tissue approach, we will examine the role of somatic mutations in enhancing immune hyperactivity and the risk for lymphoma. The staggering (7-9:1) female predominance will be elucidated through elaborate genomic, epigenomic and microbiota analyses of family trios. Finally, we will be pursuing the innovative hypothesis that the fundamental abnormalities of SLE lie within the bone marrow hematopoietic stem cells (HSCs) - from which all cells that participate in the pathogenesis of SLE originate - and establish it as a unifying pathogenetic mechanism. By a combination of novel experimental analyses with single cell genomics, multi–omics, humanized animal models, genome editing and an “organ on-a-chip” device, we will validate HSCs as a therapeutic target. The utility of SLE research extends beyond its boundaries, by providing unique insights as to how the immune system recognizes self-constituents and maintains its homeostasis, and how gender impacts on disease biology.
Max ERC Funding
2 355 000 €
Duration
Start date: 2017-09-01, End date: 2022-08-31
Project acronym NANOTHERAPY
Project A Novel Nano-container drug carrier for targeted treatment of prostate cancer
Researcher (PI) George Kordas
Host Institution (HI) "NATIONAL CENTER FOR SCIENTIFIC RESEARCH ""DEMOKRITOS"""
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary The essence of the proposal is the fabrication of multiple nano containers which exhibit double and triple stimuli response and site recognition. Specifically, the containers will be grafted by Leuprolide (LP) for prostate cancer recognition. Multiple containers will be filled by two drugs (e.g. LP and DOX) in different compartments not interacting with each other chemically (cocktail of drugs, e.g. Container1 Leuprolide (LP) and Container2 Doxorubicin (DOX)). The release can be excited by internal or external stimuli response. The internal stimuli response of our nanocontainers will require simultaneous recognition of pH, redox and/or T of the tumour. The external induction will be caused by RF excitation (hyperthermia). The nanocontainers will identify the tumour first by the agonist (LP). After trapping the container at the tumour, they will be activated by the double and triple internal excitation. This way, we achieve extremely local chemotherapy of the diseased site and the healthy organs will be untouched. Our smart nanocontainers will be tuned for prostate cancer, but our system will be evaluated for other cases such as breast cancer and thrombosis. The containers will be modified (phase transition, volume change, degradation, etc.) and deliver the drug only and if only the two sensors give positive response. The containers can be excited by external induction (Radio Frequency (hyperthermia) RF or laser light). This revolutionary strategy is necessary because the externally induced delivery methods have the disadvantage that the radiofrequency fields, the magnetic fields and the laser lights are not local but they extend over large space, larger than the size of the tumour. One cannot focus from outside the laser beam directly to the tumour only may be due to lack of imaging facilities. Our technology will prevent the release of drugs in sites where the local values correspond to the healthy tissue.
Summary
The essence of the proposal is the fabrication of multiple nano containers which exhibit double and triple stimuli response and site recognition. Specifically, the containers will be grafted by Leuprolide (LP) for prostate cancer recognition. Multiple containers will be filled by two drugs (e.g. LP and DOX) in different compartments not interacting with each other chemically (cocktail of drugs, e.g. Container1 Leuprolide (LP) and Container2 Doxorubicin (DOX)). The release can be excited by internal or external stimuli response. The internal stimuli response of our nanocontainers will require simultaneous recognition of pH, redox and/or T of the tumour. The external induction will be caused by RF excitation (hyperthermia). The nanocontainers will identify the tumour first by the agonist (LP). After trapping the container at the tumour, they will be activated by the double and triple internal excitation. This way, we achieve extremely local chemotherapy of the diseased site and the healthy organs will be untouched. Our smart nanocontainers will be tuned for prostate cancer, but our system will be evaluated for other cases such as breast cancer and thrombosis. The containers will be modified (phase transition, volume change, degradation, etc.) and deliver the drug only and if only the two sensors give positive response. The containers can be excited by external induction (Radio Frequency (hyperthermia) RF or laser light). This revolutionary strategy is necessary because the externally induced delivery methods have the disadvantage that the radiofrequency fields, the magnetic fields and the laser lights are not local but they extend over large space, larger than the size of the tumour. One cannot focus from outside the laser beam directly to the tumour only may be due to lack of imaging facilities. Our technology will prevent the release of drugs in sites where the local values correspond to the healthy tissue.
Max ERC Funding
2 000 000 €
Duration
Start date: 2009-02-01, End date: 2014-01-31
