Project of Excellence (CHRONOS)

CHRONOS BtBs UNIMIB

CHRONOS - CHRonical multifactorial disorders explored by NOvel integrated Strategies

The project of Excellence of the Department of Biotechnology and Biosciences 'CHRonical multifactorial disorders explored by NOvel integrated Strategies (CHRONOS)' is an ambitious project that has been selected and funded by the "Fund for the financing of university departments of excellence - D.L. n.232 of 11/12/2016, Vol I, Comm 314-338 ". It is a competitive funding that has rewarded the best departments with the aim of supporting innovative research, training also through the construction of infrastructure and the recruitment of qualified personnel.

The CHRONOS OBJECTIVE is to address from the point of view of pre-clinical research, teaching and third mission the study of the mechanisms underlying chronic multifactorial diseases (tumors and neurodegenerative diseases) and the aging process that shares many of the intrinsic factors, related to the genetics and physiology of individuals, and extrinsic, such as nutrition, lifestyle and environment.

The Department of Biotechnology and Biosciences intends to propose itself as a reference centre for the development of a new systemic vision of the mechanisms of initiation and chronicization of diseases and senescence in order to design new strategies of PREVENTION AND DIAGNOSIS more effective. For this reason the project foresees the creation of 4 new platforms, the recruitment of researchers and teachers, numerous exchanges and training activities with other Italian and foreign institutes and the retraining of the department's staff through dedicated paths.

The total value of the project is 7.350.000 Euro of which 6.075.00 will be financed by MIUR. The ultimate goal is to become a reference centre for the territory and attract not only researchers and scientists but also private companies interested in investing in the themes of the project.

The vision

The excellence project of the Department of Biotechnology and Biosciences starts from the awareness that 20% of the European population is over 65 years old. This trend is growing and leads to an increase in the incidence of chronic disabling diseases, such as dementia and cancer with a strong social impact related to patient management. In addition to this, more than half of the world's population is concentrated in large cities with consequent negative lifestyle effects.

The task of the research is to understand how these changes can affect biological systems and what mitigation interventions can be made. On the basis of these premises we have set ourselves the objective of addressing the study of the mechanisms underlying these chronic diseases not limited to the target cells, but considering the tissue and organism environment that surrounds them and evaluating the genetic, epigenetic, functional and modulation by environmental factors.

The study of this biological complexity requires the development of complex analytical and experimental systems and multifactorial analysis capabilities to extract information and structure it into knowledge. Starting from the information obtained, we could develop new diagnostic approaches and, above all, work on prevention, lifestyles with an impact on the territory and society.

The scientific basis of the Chronos project

The project aims to address in an integrated way the study of chronic multifactorial diseases (tumours and neurodegenerative diseases) and ageing processes.

Aging

From the biological point of view it is a progressive functional decline of the organism that increases the vulnerability to environmental hazards (stress, pathological agents) and increases the risk of contracting diseases. Ageing is a multifactorial process involving at least four fundamental cellular processes (hallmarks): metabolism, resistance to stress, regulation of gene expression and control of chromosome extremities. With advancing age, metabolic activity undergoes profound changes that reduce the efficiency with which energy is obtained from nutrients and the ability to restore the deteriorated components of the body. The regulation of gene expression and cell divisions also change and telomeres become shorter.

Tumors

These are multifactorial diseases, in which the accumulation of mutations originates a genetic variety that together with epigenetic and environmental factors results in the uncontrolled proliferation of tumor cells. Although each tumor has different characteristics, common elements, the so-called hallmarks of cancer, have been identified. Among these, genomic instability and inflammation promote the acquisition of sustained proliferative signalling, insensitivity to growth suppressors, avoidance of programmed death and acquisition of unlimited replication potential, escape from immune destruction, invasion of tissues and organs (metastasis) and deregulation of energy metabolism.

Neurodegenerative diseases

Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, etc. are chronic neurological diseases of the central nervous system due to the degeneration of specific populations of neurons and neuronal circuits responsible for these functions. Also neurodegeneration is caused by genetic, epigenetic and environmental factors that produce molecular and functional alterations that include: neuroinflammation, accumulation of aberrant non-functional proteins, alteration of neuronal transport, mitochondrial dysfunction, oxidative and metabolic stress, with consequent alteration of different cellular processes and neuronal homeostasis.

In order to influence the mechanisms that regulate ageing and the development and penetration of tumors and neurodegenerative diseases, BtBs intends to focus its research on 3 aspects common to these processes:

Multifactors

Aging, cancer and neurodegeneration are determined by genetic, epigenetic and environmental factors that influence development, aggression and drug-resistance.

Alteration of metabolism and inflammation

Aging and chronic diseases are characterized by metabolic changes and inflammatory phenomena that accompany and/or guide the development of the disease.

Biological complexity

These diseases develop by altering complex regulatory circuits characterized by different cell types and higher order structures. For example, in addition to neurons, the neurodegenerative process involves other cells (microglia, astrocytes, etc.) that actively participate in neuronal function and neurotransmission. In solid tumors, cancer cells interact with the tumor microenvironment (TME), whose components include immune system cells, blood vessels and extracellular matrix. The complex TME habitat therefore strongly influences the development and properties of the tumor. For example, TME can exert mechanical force on tumor cells by acting as a functional modulator of tumor progression, metabolic reprogramming, antioxidant defenses, and sensitivity or resistance to drug treatment.

Actions

The strategies adopted to achieve the objectives of Chronos are:

Infrastructure

Implementation of 4 LIDs and their integration.

LIDs of Advanced Multicellular Models

Equipped for the study of experimental models produced at home or obtained from specialized biobanking centers. The models will include mixed cultures, 3D cultures developed with 3D bioprinting or integrated with microfluidic systems that allow to analyze under controlled conditions (in environmental, genetic and epigenetic terms) the cellular and molecular mechanisms underlying key events in the development of diseases, such as metastatic progression.

LID of BioAnalytics and HTS

Designed for the separation of complex mixtures, such as those present in food or cellular extracts, the implementation of biochemical or cellular assays conducted on a large number of samples. It will also implement analytical techniques able to follow in molecular and structural terms the fate of individual cells and cell descendants with microscopic and post-genomic techniques with high spatial and temporal resolution.

Molecular biorecognition LIDs

In addition to the interaction between individual molecules, even in complex mixtures, such as those of biological metabolites and macromolecules obtained by extraction from natural sources, the new LID will allow the study of molecular interactions on nanostructures, including macromolecular aggregates (e.g. amyloidogenic aggregates), and on whole cells.

LID of Post-genomic data analysis and biological circuit modeling

Finalized to the analysis of big and open data related to cellular, environmental and food matrices and to the reconstruction of biological complexity through the definition of mathematical models, which allow to reproduce the molecular logic of the biological functions involved in the pathologies under study.

Staff

It is expected to acquire 1 PA and 3 RicB in 3 strategic areas: Bioinformatics and systems analysis; Analytical chemistry for complex matrices and HTS; Complex multicellular models. These figures will be fundamental to guide the ongoing transformation towards the new systemic vision of biological processes and to implement the degree and PhD courses by providing new skills also in I 4.0 as Big and Open Data analysis.

Awards

The bonus, represents the tool for the retraining of personnel and will be used to encourage the implementation of actions in 6 specific areas: project coordination, infrastructure management; support for educational activities; networking activities; dissemination and communication; fundraising and technology transfer.

Didactics

The educational development project is based on the dual track of scientific excellence and the development of skills in technology transfer, management, communication and interaction with society, and provides for coordinated activities on the two levels of training that share a strong international vocation. In this context, it envisages the activation of visiting professor positions and advanced training and teaching courses. Actions will also be implemented for the recruitment of high-profile personnel through:

  • Joint Lab and Joint PhD to be developed starting from the doctorate or in collaboration with centres such as HT and Citta della Salute.
  • Degree courses in twinning (some already active as Paris 7)
  • Visiting scientists of international renown with availability of salary enhancement and cost coverage for teaching and research activities (Wellcome Grant)

Coordinator Committee

Director and general coordinator

  • Prof. Marina Lotti

Project manager

Scientific Committee

  • Prof. Marco Vanoni (Scientific responsible)
  • Prof. Maria Pia Longhese
  • Prof. Davide Prosperi
  • Prof. Massimo Labra

Teaching Committee

  • Prof. Paola Branduardi
  • Prof. Laura Cipolla
  • Prof. Paola Fusi