Project acronym F12
Project Factor XII and the contact system:
cross-talk between thrombosis and inflammation
Researcher (PI) Hans Thomas Renné
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge.
We have previously demonstrated that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, Hereditary angioedema. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema.
The current investigations will explore roles of the FXII-driven contact system at the intersection of procoagulant and proinflammatory pathways using genetically altered murine models. We aim to understand activation, regulation and functions of the system for ischemic heart disease, vascular leakage in Hereditary angioedema, allergic airway inflammation as well as procoagulant reactions driven by bacterial infections in skin and lung.
A key aspect of this proposal will be analysis of common principles, interactions and cross-talk between coagulation and inflammation, to identify novel therapeutic targets. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases.
Summary
Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge.
We have previously demonstrated that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, Hereditary angioedema. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema.
The current investigations will explore roles of the FXII-driven contact system at the intersection of procoagulant and proinflammatory pathways using genetically altered murine models. We aim to understand activation, regulation and functions of the system for ischemic heart disease, vascular leakage in Hereditary angioedema, allergic airway inflammation as well as procoagulant reactions driven by bacterial infections in skin and lung.
A key aspect of this proposal will be analysis of common principles, interactions and cross-talk between coagulation and inflammation, to identify novel therapeutic targets. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases.
Max ERC Funding
1 488 780 €
Duration
Start date: 2013-08-01, End date: 2018-07-31
Project acronym NOVEL_MYOKINE
Project Irisin - a novel myokine protective against metabolic disease
Researcher (PI) Pontus Almer Boström
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Cardiovascular disease and diabetes constitute the major disease burden in the western world with growing morbidity. Exercise is known to ameliorate many of the key processes in the pathogenesis of these diseases, but the underlying mechanism is not clear. Especially little is known about how exercise affects non-muscle tissues such as the heart, fat and liver. Knowledge of such pathways could lead to new therapeutic possibilities for diabetes and cardiovascular diseases.
I have recently discovered a new hormone, named Irisin. Irisin is regulated by PGC1α, secreted from muscle to plasma after exercise and promotes the formation of brown fat via an unknown receptor. Furthermore, irisin is 100% conserved between mice and humans at the amino acid level (89% identity between zebfrafish and human). Nanomolar levels of this protein increase uncoupling protein 1 (UCP1) in cultures of primary white fat cells by 50 fold or more, resulting in very large increases in uncoupled respiration. Perhaps more remarkable, in vivo delivery of irisin stimulates a robust increase in UCP1, increased energy expenditure and reversal of type II diabetes in high fat fed mice. It is thus likely that irisin is responsible for at least some of the beneficial effects of exercise on the browning of adipose tissues and increases in energy expenditure. The therapeutic potential of irisin is obvious; it is a conserved endogenous polypeptide, induced with exercise and with powerful anti-diabetic properties. Irisin could, for example, be administered exogenously, or the secretion of irisin could be enhanced. These approaches, however, require additional studies, and my aim in this project is to advance the knowledge around irisin for future therapeutic testing.
Given success of the ERC grant application, I will move from Harvard/Boston 2012 and start my lab at the department of Cell- and Molecular Biology, Karolinska Institute, Sweden. As seen in my list of publication, Im well prepared for this task
Summary
Cardiovascular disease and diabetes constitute the major disease burden in the western world with growing morbidity. Exercise is known to ameliorate many of the key processes in the pathogenesis of these diseases, but the underlying mechanism is not clear. Especially little is known about how exercise affects non-muscle tissues such as the heart, fat and liver. Knowledge of such pathways could lead to new therapeutic possibilities for diabetes and cardiovascular diseases.
I have recently discovered a new hormone, named Irisin. Irisin is regulated by PGC1α, secreted from muscle to plasma after exercise and promotes the formation of brown fat via an unknown receptor. Furthermore, irisin is 100% conserved between mice and humans at the amino acid level (89% identity between zebfrafish and human). Nanomolar levels of this protein increase uncoupling protein 1 (UCP1) in cultures of primary white fat cells by 50 fold or more, resulting in very large increases in uncoupled respiration. Perhaps more remarkable, in vivo delivery of irisin stimulates a robust increase in UCP1, increased energy expenditure and reversal of type II diabetes in high fat fed mice. It is thus likely that irisin is responsible for at least some of the beneficial effects of exercise on the browning of adipose tissues and increases in energy expenditure. The therapeutic potential of irisin is obvious; it is a conserved endogenous polypeptide, induced with exercise and with powerful anti-diabetic properties. Irisin could, for example, be administered exogenously, or the secretion of irisin could be enhanced. These approaches, however, require additional studies, and my aim in this project is to advance the knowledge around irisin for future therapeutic testing.
Given success of the ERC grant application, I will move from Harvard/Boston 2012 and start my lab at the department of Cell- and Molecular Biology, Karolinska Institute, Sweden. As seen in my list of publication, Im well prepared for this task
Max ERC Funding
1 999 433 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym TUMORGAN
Project Exploring the tumor as a communicating organ
Researcher (PI) Jan Kristian Pietras
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary The failure to bring about major advances in cancer care over the past decades points to the need for a revolution in our view of cancer as a disease caused by a lack of growth control in malignant cells. We propose that a tumor should be considered a communicating organ made of multiple cell types that collectively evolve into a clinically manifested and deadly disease. With this proposition follows that targeting of communication within tumors to attenuate the support from the stroma is the only viable strategy to achieve long term therapeutic benefit. Our research addresses the need to study the cellular context of cancer with a higher resolution. The general aim of the proposed work is to identify subsets of different cell types within the tumor stroma that hold utility as therapeutic targets and biomarkers. The work will be performed through a set of experiments bridging basic biology, pre-clinical studies and molecular oncology.
The specific aims are:
1) Identification of cellular subsets of the tumor vasculature
2) Investigation of the therapeutic utility of cellular subsets of the tumor vasculature
3) Exploration of the potential of cellular subsets of the tumor vasculature as biomarkers
The aims of the study will be pursued through a series of methodological refinements. Firstly, identification of novel components of tumors will be achieved by the assembly of a mouse genetic tool box enabling isolation, lineage tracing and functional studies. Secondly, single cell transcriptome sequencing will be performed to identify cellular subsets using materials from both mouse and man. Thirdly, the utility as therapeutic targets of the new cellular subsets will be assessed using a live imaging approach. Fourthly, the clinical significance of the new cellular subsets will be investigated using exclusive patient materials.
Taken together, the information provided by our studies will enable us to take cancer therapy into a new era of personalized medicine.
Summary
The failure to bring about major advances in cancer care over the past decades points to the need for a revolution in our view of cancer as a disease caused by a lack of growth control in malignant cells. We propose that a tumor should be considered a communicating organ made of multiple cell types that collectively evolve into a clinically manifested and deadly disease. With this proposition follows that targeting of communication within tumors to attenuate the support from the stroma is the only viable strategy to achieve long term therapeutic benefit. Our research addresses the need to study the cellular context of cancer with a higher resolution. The general aim of the proposed work is to identify subsets of different cell types within the tumor stroma that hold utility as therapeutic targets and biomarkers. The work will be performed through a set of experiments bridging basic biology, pre-clinical studies and molecular oncology.
The specific aims are:
1) Identification of cellular subsets of the tumor vasculature
2) Investigation of the therapeutic utility of cellular subsets of the tumor vasculature
3) Exploration of the potential of cellular subsets of the tumor vasculature as biomarkers
The aims of the study will be pursued through a series of methodological refinements. Firstly, identification of novel components of tumors will be achieved by the assembly of a mouse genetic tool box enabling isolation, lineage tracing and functional studies. Secondly, single cell transcriptome sequencing will be performed to identify cellular subsets using materials from both mouse and man. Thirdly, the utility as therapeutic targets of the new cellular subsets will be assessed using a live imaging approach. Fourthly, the clinical significance of the new cellular subsets will be investigated using exclusive patient materials.
Taken together, the information provided by our studies will enable us to take cancer therapy into a new era of personalized medicine.
Max ERC Funding
1 498 150 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
