Research Project information
Principal researcher: Dr Vincenzo Costanzo
Institute: IFOM – The FIRC Institute of Molecular Oncology, Milan, Italy
Cost: £99,936 over 36 months
Start Date: December 2016
What are the researchers proposing to do?
The research team will test the hypothesis that ATM (the protein which is missing or not functioning completely in A-T) controls the chemical reactions required for the production of nucleotides, which are the building blocks of DNA and other cellular components. The impairment of these processes might be one of the causes of the health problems associated with A-T. Nucleotides are essential components of DNA and RNA, which are molecules that store and generate the information needed for all cellular functions. Lack in nucleotide production might impair the production of other cellular components, such as proteins, and lead to poor DNA repair and DNA duplication causing problems in cell growth, cell duplication and cell survival under stress. These defects might be responsible for some of the problems typical in A-T patients such as neurological degeneration, immunodeficiency, radiation sensitivity, pulmonary infections and increased risk for cancer. Nucleotide defects could be the target of novel strategies aimed at restoring their levels in order to correct the cellular defects present in A-T cells.
ATM is known to regulate the activation of a series of chemical reactions that protect cells from external and internal agents that cause damage to cellular pieces such as DNA. In the past few years the team in Milan have identified important targets of ATM action. In these studies they found that ATM regulates the pentose phosphate pathway (PPP), a cellular process involved in the metabolism of sugar. This process is the major source of cellular parts such as nucleotides, which are required to make and repair DNA. Preliminary experiments recently confirmed these findings and indicated the presence of defects in nucleotide concentration in cells derived from patients suffering from A-T.
How will the research be done?
The team will use several scientific methods to study the metabolic steps of the nucleotide pathways in A-T cells and study novel strategies to try to restore nucleotide balance in A-T cells. They will study the molecular reactions required to produce nucleotides, which could be directly controlled by ATM. This will provide further understanding of how these defects occur and how they could be corrected. The relevance of these metabolic alterations will be directly tested by manipulating and restoring altered metabolic pathways in A-T cells with existing compounds that are already known to impact on nucleotide metabolism. These studies will be important to understand how ATM controls cell survival and might be helpful to design novel therapeutic interventions to restore cellular functions controlled by ATM, which are altered or absent in A-T cells, bypassing the requirement for the ATM gene.
How could it make a difference to the lives of those affected by A-T?
The team hope that their studies on A-T cells will provide fundamental clues on cellular processes impaired in A-T and will uncover compounds able to modify and correct the A-T cellular defects. This work could therefore provide essential information that will assist clinicians in the design of therapeutic interventions with such drugs and compounds. If successful this strategy could help to delay or minimise the impact of some of the clinical problems associated with A-T on patients.
This project was made possible thanks to the funds raised by the 2016 Scumrun participants and donations made in memory of Stephen Green. Stephen was riding for Action for A-T when he suffered a fatal heart attack during the 2015 Prudential Ride 100 cycle event.