Project acronym IMAGO
Project Imaging regulatory pathways of angiogenesis
Researcher (PI) Michal Neeman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary Homeostasis of multicellular tissues relies on accurate match of vascular supply and drain to the needs of the tissue. Multiple pathways are involved in detection, signalling and execution of the required steps involved in organization of blood and lymphatic vessels during embryonic development. Similar mechanisms are utilized for overcoming changes in tissue requirements also in adult tissues and in pathological processes. The goal of this work is to reveal the dynamic forces that shape the blood vessels during angiogenesis. In particular, we would like to explore the impact of interstitial convective flow in dynamic imprinting of growth factor signalling, thereby regulating vascular patterning. Angiogenesis is explored here as an example for a possible general role for interstitial convection of growth factors in determination of the fine spatial patterning of tissue morphogenesis in vertebrates. To achieve this goal, we will develop multi-modality tools for imaging the regulation of vascular patterning. In vivo imaging will then be utilized for mapping vascular patterning in pathological and physiological angiogenesis including tumours, wound repair, the preovulatory ovarian follicle and foetal implantation sites. Whole body optical, CT, ultrasound and MRI will be applied for non-invasive imaging of deep organs. Microscopic morphometric and molecular information will be derived from the macroscopic imaging data, using selective molecular imaging approaches and functional imaging tools with specific pharmacological models that will be developed to account for interstitial convective flow. Intravital two photon microscopy and fluorescence endoscopy will be used for high resolution evaluation of vascular patterning. The evaluation of novel mechanisms for spatial regulation of intercellular growth factor signalling, will allow us to define new potential targets for intervention, and to develop new tools for preclinical and clinical imaging of angiogenesis.
Summary
Homeostasis of multicellular tissues relies on accurate match of vascular supply and drain to the needs of the tissue. Multiple pathways are involved in detection, signalling and execution of the required steps involved in organization of blood and lymphatic vessels during embryonic development. Similar mechanisms are utilized for overcoming changes in tissue requirements also in adult tissues and in pathological processes. The goal of this work is to reveal the dynamic forces that shape the blood vessels during angiogenesis. In particular, we would like to explore the impact of interstitial convective flow in dynamic imprinting of growth factor signalling, thereby regulating vascular patterning. Angiogenesis is explored here as an example for a possible general role for interstitial convection of growth factors in determination of the fine spatial patterning of tissue morphogenesis in vertebrates. To achieve this goal, we will develop multi-modality tools for imaging the regulation of vascular patterning. In vivo imaging will then be utilized for mapping vascular patterning in pathological and physiological angiogenesis including tumours, wound repair, the preovulatory ovarian follicle and foetal implantation sites. Whole body optical, CT, ultrasound and MRI will be applied for non-invasive imaging of deep organs. Microscopic morphometric and molecular information will be derived from the macroscopic imaging data, using selective molecular imaging approaches and functional imaging tools with specific pharmacological models that will be developed to account for interstitial convective flow. Intravital two photon microscopy and fluorescence endoscopy will be used for high resolution evaluation of vascular patterning. The evaluation of novel mechanisms for spatial regulation of intercellular growth factor signalling, will allow us to define new potential targets for intervention, and to develop new tools for preclinical and clinical imaging of angiogenesis.
Max ERC Funding
2 278 344 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym TROJA
Project Targeting Receptors Of Jointly Assembled Ligand-Drug Constructs
Researcher (PI) Søren Kragh Moestrup
Host Institution (HI) AARHUS UNIVERSITET
Call Details Advanced Grant (AdG), LS7, ERC-2008-AdG
Summary The TROJA proposal is an investigative bioengineering study of the exploitation of specific endocytic receptors for targeting small molecule drugs to specific cells in order to improve medical therapy. This is a new approach with scientific roots in the basic research on endocytic receptors and protein expression carried out in the laboratory of the applicant. The major line of the proposal concerns the construction of combinatory drugs for targeting the haptoglobin (Hp)-hemoglobin receptor CD163 (Kristiansen et al., Nature 409:198-201) expressed in the monocyte-macrophage system. The platform may apply to a broad spectrum of diseases such as inflammatory diseases, various infections and certain cancers which all have CD163-expressing macrophages or malignant derivatives as key cell type in the pathogenesis of the disease. Dependent of the above-mentioned diseases to be treated, the drugs are intended to have anti-inflammatory, microbiotic or cytostatic effects. Efficacy of the combinatory drug will be investigated in monocytes/macrophages, CD163-transfected cells and as well as in suitable animal models including transgenic animals. Another and minor line of the proposal concerns the construction of combinatory drugs for targeting a very recently discovered Hp-Hb receptor expressed in trypanosomes (Vanhollebeke et al., Science, in press) causing sleeping sickness. Both lines of this research proposal will take advantage of established recombinant protein expression methods and chemical coupling technology to construct jointly assembled ligand-drugs complexes. In terms of drug efficacy and toxicity, the aim is to design combinatory products that remain largely inactive in their receptor-binding form, but upon release in the cells or parasites the active small molecule components become active. The discovery of such a Trojan horse platform for cellular drug entry may have major implications for future drug development and for new applications of existent drugs.
Summary
The TROJA proposal is an investigative bioengineering study of the exploitation of specific endocytic receptors for targeting small molecule drugs to specific cells in order to improve medical therapy. This is a new approach with scientific roots in the basic research on endocytic receptors and protein expression carried out in the laboratory of the applicant. The major line of the proposal concerns the construction of combinatory drugs for targeting the haptoglobin (Hp)-hemoglobin receptor CD163 (Kristiansen et al., Nature 409:198-201) expressed in the monocyte-macrophage system. The platform may apply to a broad spectrum of diseases such as inflammatory diseases, various infections and certain cancers which all have CD163-expressing macrophages or malignant derivatives as key cell type in the pathogenesis of the disease. Dependent of the above-mentioned diseases to be treated, the drugs are intended to have anti-inflammatory, microbiotic or cytostatic effects. Efficacy of the combinatory drug will be investigated in monocytes/macrophages, CD163-transfected cells and as well as in suitable animal models including transgenic animals. Another and minor line of the proposal concerns the construction of combinatory drugs for targeting a very recently discovered Hp-Hb receptor expressed in trypanosomes (Vanhollebeke et al., Science, in press) causing sleeping sickness. Both lines of this research proposal will take advantage of established recombinant protein expression methods and chemical coupling technology to construct jointly assembled ligand-drugs complexes. In terms of drug efficacy and toxicity, the aim is to design combinatory products that remain largely inactive in their receptor-binding form, but upon release in the cells or parasites the active small molecule components become active. The discovery of such a Trojan horse platform for cellular drug entry may have major implications for future drug development and for new applications of existent drugs.
Max ERC Funding
2 400 000 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
