To facilitate communication and project management, PRIME is structured into 8 Work packages (WPs), each one with a WP leader, who supervises the work carried out closely and directly interacts with the project office. Varying numbers of parties are further involved in contributing to the WPs, but there is always a lead beneficiary.
Please click on the name of the Work Package for a more detailed description.
The aim of WP1 is to substantially expand the knowledge on the links between somatic insulin-related morbidity and brain disorders and related traits. Analyses will be based on large clinical and biological data sets available to the partners. Findings from WP1 will inform WP3, WP4, WP5, and WP6.
The specific objectives of WP1 are the following:
- To perform epidemiological investigations of bidirectional associations between diagnoses of somatic insulin-related diseases and of compulsive, cognitive, and other brain-related disorders by estimating incidence and risk across the lifespan and evaluating the modifying effects of gender, lifestyle and socioeconomic factors on these associations
- To estimate familial co-aggregation of such somatic and brain-related insulinopathies at the population level
- To observe subclinical signs and symptoms linked to insulin dysregulation, which is key to early diagnosis and timely personalized treatment or prevention of insulin-related multimorbidity
- To investigate associations of altered insulin signaling with compulsivity and cognitive rigidity disorders and
related behavioural population traits, and with Romano Ward Syndrome (RWS)
WP2 will build upon the evidence indicating a role of insulin signaling in the multimorbid occurrence of DM2/obesity/metabolic syndrome, compulsive behaviour, and cognitive rigidity. WP2 will use in vivo mouse models to detail the cellular and molecular causative mechanisms involving insulin and test the feasibility of pharmacological and nonpharmacological therapeutic approaches in a lifespan perspective in both male and female animals. WP2 will evaluate three selected mouse models and subsequently validate candidate treatments in those experimental models characterized by the highest construct (etiological isomorphism) and face (symptom similarity) validities. Candidate treatments will complement human studies (as detailed in WP5) and focus on: (a) drug agonists acting on KCNQ1 as a primary causative factor; (b) repurposing of DM2 medications (metformin) to treat insulin-related CNS disturbances; (c) physical exercise as a proxy for lifestyle modification.
The specific objectives of WP2 are the following:
- To verify the association between mental (compulsivity, cognitive rigidity/learning deficits) and somatic (DM2/ obesity) disorders in two mouse models selected based on consistent alterations in insulin signaling
- To assess the association between mental (compulsivity, cognitive rigidity/learning deficits) and somatic (DM2/obesity) disorders with Aβ aggregation using the APP/PS1 mutant mouse model
- To provide proof-of-concept data, in the most promising animal model(s) investigated under the first 2 objectives, for pharmacological and non-pharmacological therapeutic approaches
- To delineate the molecular mechanisms potentially affecting peripheral and central insulin signaling and those underlying the therapeutic potential of the treatments investigated
Patient-derived iPSCs, genome editing, and neuronal differentiation of human iPSCs will be used to create an in vitro model of human neurons, which can be manipulated to delineate the causal mechanisms underlying insulin-related comorbidities.
The specific objectives of WP3 are the following:
- To identify molecular and cellular mechanisms underlying mental and somatic insulin multimorbidity
- To prove the relevance of mechanisms for comorbidity development identified by our partners in WP2 by testing whether the loss of KCNQ1 results in changes in insulin-related mechanisms in human neurons
- To validate novel treatment targets to develop novel pharmacological as well as non-pharmacological preventative and therapeutic strategies
While the molecular mechanisms linking insulin signaling to the somatic diseases have been investigated extensively, detailed knowledge about the insulin-related pathways contributing to the comorbidity with compulsivity disorders and AD is still largely lacking. Here we work to define and elucidate the causative molecular pathways underlying insulin multimorbidity in powerful study designs exploiting large existing databases. Based on these results, we will identify novel biomarkers and prioritize new candidate drug targets, considering gender and lifespan aspects.
The specific objectives of WP4 are the following:
- To determine the extent of genetic overlap between somatic and brain insulinopathies by combining the world-wide largest genetic data sets and exploring novel insulinopathies based on genetic correlation
- To identify genetic variants, genes, and gene-sets as well as epigenetic modifications that are most important to insulin multimorbidity
- To discover the molecular mechanisms underlying insulin multimorbidity and identify candidate biomarkers and new candidate drug targets
The new insights into insulin-related morbidity expose the great need for novel approaches to treatment and prevention of multimorbidity. In this WP, we aim to provide evidence for the repurposing of existing pharmacological and lifestyle-based treatments, and develop novel approaches for prediction and treatment of insulin-related multimorbidity. To accomplish this, WP5 will capitalize on large population registries and cohorts with existing information on treatment and lifestyle. Moreover, in the scope of an observational study, new data will be collected through mHealth approaches to analyze the interplay between physical activity, dietary-nutritional patterns, and cognitive/behavioural measures linked to compulsivity and behavioural rigidity.
The specific objectives of WP5 are the following:
- To assess the impact of insulin and IGF signaling modifiers on the risk to develop comorbidities associated with altered insulin signaling
- To study the effect of lifestyle on insulin-related trait and multimorbidity patterns
- To evaluate KCNQ1 as a novel treatment target for DM2 and insulin-related brain morbidity
- To create statistical predictive models based on causative mechanisms to support a diagnosis of multimorbidity and determine the probability of treatment success
The overall goal of WP6 is to develop and execute a detailed plan for the dissemination and exploitation of PRIME results, incorporating communication to diverse target groups, including the general public, health professionals, and policy makers. For insulin-related multimorbidity, there is a particular need for dissemination in the area of mental health, as brain-related insulinopathies are not well-documented yet and are normally not considered when a diagnosis of a somatic insulinopathy is made. Our work will inform the clinical management of insulin-related multimorbidities and public health policy as well as raise awareness in the public.
The specific objectives of WP6 are the following:
- To develop a communication and outreach plan for activities directed at communicating knowledge of insulinopathies on body and brain across the lifespan, aimed at to health professionals, patient associations, and end-users
- To develop and implement an exploitation strategy for PRIME products
- To carry out dissemination activities to enhance awareness of insulin-related multimorbidity amongst the legislative, medical, and scientific communities and create policy documents
- To review existing European clinical guidelines (e.g. NICE, EMA, and other clinical guidelines) for DM2/metabolic syndrome/obesity, compulsivity disorders, and dementias/AD, and create addenda using the acquired data to recommend changes to such guidelines
- To improve the management of these diseases and their comorbidities and recommend implementation steps as to how this can be adopted in clinical practice
Beyond the scientific expertise provided by the participating sites, the success of PRIME further relies on appropriate, specialized training and mentoring provided to its researchers, the effective coordination of training activities across the sites, and the appropriate ethical conduct of all parts of the program. We strive to achieve the highest standards for both training and ethical aspects within PRIME.
The specific objectives of WP7 are the following:
- To provide specialized training on project topics for all PRIME researchers
- To foster the career development of all PRIME early career researchers, incorporating mentoring elements designed to optimally support the specific needs of both female and male early career researchers
- To monitor and support project-wide ethical conduct
Effective project management is a central element of successful research. This is because large research projects entail a lot of administrative work.
The specific objectives of WP8 are the following:
- To help PRIME achieve its objectives and to deliver in time, budget and quality its milestones and deliverables
- To help the consortium abide by the regulations and contractual obligations according to the grant agreement, its annexes and the consortium agreement
- To look after the project’s finances and to report them properly to the European Commission
- To establish a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project
- To preserve the rights of the partners regarding intellectual property and to act as a mediator in case of disputes