HORIZON EUROPE
Europeo
Specific Challenge:Amongst the commonalities of neurodegenerative diseases such as Parkinson's disease (PD), are bioenergetic failure and oxidative stress, both of which reflect the dysfunction of mitochondria within neural and glial cells. As such, a detailed understanding of mitochondrial dysfunction in the brain in the context of ageing, injury by misfolded protein toxicity, and genetic factors associated with neurodegeneration holds much promise for the development of therapeutic interventions that could impact multiple neurodegenerative disease states.
The overall challenge of the topic is to develop an unprecedented appreciation of the evolution of mitochondrial dysfunction in models of PD in order to understand if dysfunction is a driver of disease progression. A key goal is to develop an unprecedented appreciation of mitochondrial function in an in vivo model of neurodegenerative disease, which is currently lacking. Other challenges to be addressed within this topic are to quantitatively dissect changes in mitochondrial function in in vitro and in vivo models (including brain slices) and through mechanistic computational models of PD; and to understand the...
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Specific Challenge:Amongst the commonalities of neurodegenerative diseases such as Parkinson's disease (PD), are bioenergetic failure and oxidative stress, both of which reflect the dysfunction of mitochondria within neural and glial cells. As such, a detailed understanding of mitochondrial dysfunction in the brain in the context of ageing, injury by misfolded protein toxicity, and genetic factors associated with neurodegeneration holds much promise for the development of therapeutic interventions that could impact multiple neurodegenerative disease states.
The overall challenge of the topic is to develop an unprecedented appreciation of the evolution of mitochondrial dysfunction in models of PD in order to understand if dysfunction is a driver of disease progression. A key goal is to develop an unprecedented appreciation of mitochondrial function in an in vivo model of neurodegenerative disease, which is currently lacking. Other challenges to be addressed within this topic are to quantitatively dissect changes in mitochondrial function in in vitro and in vivo models (including brain slices) and through mechanistic computational models of PD; and to understand the impact on the degeneration of neurons and/or glia.
There is a growing appreciation of the impact of glial cells (astrocytes, oligodendrocytes and microglia) in neurodegeneration, so it would be valuable to investigate mitochondrial dysfunction in several cell types. There is also the opportunity to investigate mitochondrial function in neural cells derived from human sources, both from patients and unaffected individuals.
Identification of the key molecular drivers of mitochondrial dysfunctions in the disease models will provide a unique scaffold to enable the discovery and development of new therapeutics to halt neurodegenerative disease progression.
It is anticipated that the topic will lead to the identification of key molecular drivers which will provide a foundation for the identification and validation of new drug targets, facilitating innovative therapeutic approaches within the neurodegeneration field. Moreover, mitochondrial abnormalities serve as a connecting theme between several neurodegenerative diseases, with a direct link to several processes known to be impaired in neurodegeneration such as bioenergetics and misfolded protein toxicity. Therefore, the learnings are anticipated to also feed into the understanding of the role of mitochondrial dysfunctions in other neurodegenerative diseases such as Alzheimer’s disease (AD).
Scope:The overall scope of the project generated by this topic is to identify and understand the impact of mitochondrial dysfunction in in vitro and in vivo models of neurodegenerative diseases, incorporating core characteristics of neurodegeneration such as protein misfolding. Understanding if dysfunction is a driver of disease progression, and the detailed mechanisms responsible for it, will enable the exploration of novel targets for therapeutic approaches to neurodegenerative diseases.
The scope will be reached by a scientifically robust strategy building on established and innovative PD models, and the appropriate technology experience within the consortium. More specifically, this will include addressing the following objectives:
In vitro
In established and innovative in vitro models of PD in neurons, microglia, oligodendrocytes and/or astrocytes, understand the impact of mitochondrial dysfunction (such as respiratory function, biogenesis, trafficking, fission, fusion and mitophagy) on the development/severity of the disease phenotype and identify key molecular drivers of these dysfunctions. Assessment of correlation between morphology and function should be included to ease later interpretation of morphological observations in vivo.Among others, the in vitro phenotype would ideally include a demonstration of mitochondrial dysfunction induced by α-synuclein or tau in a humanised model system such as induced pluripotent stem cells (iPSCs) which allow the study of both neurons and glia (astrocytes, oligodendrocytes and microglia) individually, but also in co-cultures to study interactions and cross-talk. These cellular models would then be further developed into a robust model for therapeutic target identification. Models could potentially include organotypic slice cultures including those incorporating prion-like spreading of misfolded proteins. Assessment of correlation between morphology and function should be included to ease later interpretation of morphological observations in vivo.Neurodegeneration is a phenomenon directly associated with ageing, yet most in vitro cell-based models use neonatal tissues as a source of primary cells. Moreover, iPSCs essentially have their biological clock reset, thus eliminating elements of ageing in the model. Incorporating a component affecting mitochondrial ageing as a model variable would be a valuable addition to the in vitro approach. In vivo
In a well characterised, robust in vivo PD model, investigate if mitochondrial dysfunction can be identified. Understand the impact of these changes on disease progression such as neuronal and synaptic health, as well as the potential for their therapeutic modulation. While many in vivo models of PD exist, convenient models using transgenic animals already aged before the start of the project or injection of fibrillary forms of disease-associated proteins as a seeding mechanism to trigger neurodegeneration would be the most appropriate. These models typically develop disease pathology over a time frame suitable for the studies proposed here. In silico
Reconstruct a mechanistic computational model of mitochondrial function to account for the gene products of each gene associated with mitochondria and closely associated organelles. Integrate the experimental data from the in vitro and in vivo experiments to generate control and neurodegenerative computational models. Quantify the relative contribution of abnormal respiratory function, biogenesis, dynamics (axonal transport, fission, fusion), and mitophaghy to mitochondrial dysfunction.
Expected Impact:Progressive neurodegenerative diseases represent a large and growing burden. Despite a considerable investment in research aimed at understanding and treating neurodegeneration, the lack of disease-modifying therapies remains notable. Recognising this gap, the treatment of neurodegenerative disease is a clearly-identified goal of IMI2 JU, and the expected impact of the project to be generated by this topic is closely aligned with the overall goal.
There is considerable evidence implicating mitochondrial dysfunction in the pathogenesis of a number of progressive neurodegenerative diseases, including Parkinson’s disease, but no efficacious treatments have been developed based on this knowledge.
By developing a set of validated cellular assays, organotypic brain slice models and in vivo tools, the project will remove an important barrier that has limited the systematic exploration of mitochondrial dysfunction in neurodegenerative disease. A clear identification of the specific mitochondria dysfunctions (such as respiratory function, biogenesis, trafficking, fission, fusion or mitophagy) contributing to neurodegeneration will enable the discovery of novel targets for intervention.
By taking advantage of recent advances in the understanding of mechanisms that control mitochondrial dynamics and using innovative technologies to access mitochondrial dysfunction (e.g. axonal transport and fusion/fission in highly relevant model systems), this approach should provide unprecedented insights into the causal link between mitochondrial dysfunction and neurodegeneration.
SMEs can be of great benefit to IMI2 JU projects and, inter alia, strengthen the competitiveness and industrial leadership of Europe. Their involvement might offer a complementary perspective to industry and academia, and help deliver the long-term impact of the project. For these reasons, applicants should consider engaging SMEs throughout the proposal.
The project learnings will strongly aid neurodegenerative disease understanding and the identification of novel targets, giving academics/SMEs/pharmaceutical companies new options for treatments of diseases with mitochondrial dysfunction, such as PD. Moreover it would encourage a renewed investment in developing drugs for neurodegenerative disorders for which there is a high unmet medical need. In particular, biotech SMEs will be able to ‘stress-test’ their technologies in a non-competitive, open innovation environment, which will greatly facilitate the development of novel and important therapeutics.
Thus, it can be anticipated that the results of the project will benefit patients and society through the accelerated discovery of new drugs and therapies for neurodegenerative diseases.
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Características del consorcio
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La ayuda es de ámbito europeo, puede aplicar a esta linea cualquier empresa que forme parte de la Comunidad Europea.
Características del Proyecto
Los costes de personal subvencionables cubren las horas de trabajo efectivo de las personas directamente dedicadas a la ejecución de la acción. Los propietarios de pequeñas y medianas empresas que no perciban salario y otras personas físicas que no perciban salario podrán imputar los costes de personal sobre la base de una escala de costes unitarios
Los otros costes directos se dividen en los siguientes apartados: Viajes, amortizaciones, equipamiento y otros bienes y servicios. Se financia la amortización de equipos, permitiendo incluir la amortización de equipos adquiridos antes del proyecto si se registra durante su ejecución. En el apartado de otros bienes y servicios se incluyen los diferentes bienes y servicios comprados por los beneficiarios a proveedores externos para poder llevar a cabo sus tareas
La subcontratación en ayudas europeas no debe tratarse del core de actividades de I+D del proyecto. El contratista debe ser seleccionado por el beneficiario de acuerdo con el principio de mejor relación calidad-precio bajo las condiciones de transparencia e igualdad (en ningún caso consistirá en solicitar menos de 3 ofertas). En el caso de entidades públicas, para la subcontratación se deberán de seguir las leyes que rijan en el país al que pertenezca el contratante
Características de la financiación
The IMI2 13th Call for proposals topic text as well as the Call Conditions are available here.
The budget breakdown for this Call is given at the end of the Call topics text, in the Call Condtions section, as well as the following information:
1. Eligible countries: described in article 10(2) of the Rules for participation in Horizon 2020 and in article 1 of the Commission Delegated Regulation related to IMI JU.
2. Eligibility and admissibility conditions: described in the IMI2 Manual for evaluation, submission and grant award. See also the Commission Delegated Regulation related to IMI JU.
Proposal page limits and layout: Please refer to Part B of the proposal template in the submission tool below.
3. Evaluation:
Submission and evaluation process, including evaluation criteria and procedure, scoring and threshold are described in the IMI2 Manual for submission, evaluation and grant award. See also the proposal templates for your specific action in section 5, below.
4. Indicative time for evaluation and grant agreement:
Notification of outcomes of stage 1 evaluations: maximum 5 months from deadline for submitting proposals.
Notification of outcomes of stage 2 evaluations: maximum 5 months from deadline for submitting full p... Please read carefully all provisions below before the preparation of your application.
The IMI2 13th Call for proposals topic text as well as the Call Conditions are available here.
The budget breakdown for this Call is given at the end of the Call topics text, in the Call Condtions section, as well as the following information:
1. Eligible countries: described in article 10(2) of the Rules for participation in Horizon 2020 and in article 1 of the Commission Delegated Regulation related to IMI JU.
2. Eligibility and admissibility conditions: described in the IMI2 Manual for evaluation, submission and grant award. See also the Commission Delegated Regulation related to IMI JU.
Proposal page limits and layout: Please refer to Part B of the proposal template in the submission tool below.
3. Evaluation:
Submission and evaluation process, including evaluation criteria and procedure, scoring and threshold are described in the IMI2 Manual for submission, evaluation and grant award. See also the proposal templates for your specific action in section 5, below.
4. Indicative time for evaluation and grant agreement:
Notification of outcomes of stage 1 evaluations: maximum 5 months from deadline for submitting proposals.
Notification of outcomes of stage 2 evaluations: maximum 5 months from deadline for submitting full proposals.
Signature of grant agreements: maximum 3 months from the date of informing successful applicants.
5. Proposal templates, evaluation forms and model grant agreements (MGA), clinical trials template:
IMI2 Research and Innovation Action (IMI2-RIA) and Innovation Action (IMI2-IA):
Proposal templates are available after entering the submission tool.
Standard evaluation form RIA
IMI2 Model Grant Agreement:
Members of consortium are required to conclude a consortium agreement prior to the signature of the grant agreement.
Clinical trial template:
The Clinical Trial template is compulsory at stage 2 only !
IMI2 Coordination and Support Action (IMI2-CSA):
Proposal templates are available after entering the submission tool.
Standard evaluation form CSA
IMI2 Model Grant Agreement:
Members of consortium are required to conclude a consortium agreement prior to the signature of the grant agreement.
Clinical trial template:
The Clinical Trial template is compulsory at stage 2 only !
6. Open access must be granted to all scientific publications resulting from Horizon 2020 actions.
Where relevant, proposals should also provide information on how the participants will manage the research data generated and/or collected during the project, such as details on what types of data the project will generate, whether and how this data will be exploited or made accessible for verification and re-use, and how it will be curated and preserved.
Open access to research data
The Open Research Data Pilot has been extended to cover all Horizon 2020 topics for which the submission is opened on 26 July 2016 or later. Projects funded under this topic will therefore by default provide open access to the research data they generate, except if they decide to opt-out under the conditions described in Annex L of the H2020 main Work Programme. Projects can opt-out at any stage, that is both before and after the grant signature.
Note that the evaluation phase proposals will not be evaluated more favourably because they plan to open or share their data, and will not be penalised for opting out.
Open research data sharing applies to the data needed to validate the results presented in scientific publications. Additionally, projects can choose to make other data available open access and need to describe their approach in a Data Management Plan.
Projects need to create a Data Management Plan (DMP), except if they opt-out of making their research data open access. A first version of the DMP must be provided as an early deliverable within six months of the project and should be updated during the project as appropriate. The Commission already provides guidance documents, including a template for DMPs. See the Online Manual.
Eligibility of costs: costs related to data management and data sharing are eligible for reimbursement during the project duration.
The legal requirements for projects participating in this pilot are in the article 29.3 of the Model Grant Agreement.
7. Additional documents:
Summary of the most relevant provisions for participating in IMI2 actions
IMI2 - 2nd Amendment to the Annual Work Plan 2017
IMI2 Regulators Guidance tool for researchers
IMI JU derogation to H2020 Rules for Participation
Horizon 2020 Rules for Participation
Horizon 2020 Regulation of Establishment
Horizon 2020 Specific Programme
Members of consortium are required to conclude a consortium agreement prior to the signature of the grant agreement.
Información adicional de la convocatoria
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