Objective
Aim of the project is the definition of the molecular requirements for the generation and intracellular transmission of the apoptotic signal from surface receptors in transformed cells.
As surface receptor-mediated apoptosis induction is a key mechanism exploited by immune effect cells to eliminate cancer cells, understanding the biochemical nature of the apoptotic signal is of major relevance in cancer biology. The model we are using in the human system is represented by two highly related receptors, widely expressed on a variety of normal and transformed cells, the tumour necrosis factor receptor type 1 (TNF-R1) and the Fas/APO-1 receptor. Crosslinking of TNF-R1 and Fas/APO-1 by their specific ligands triggers a cascade of still largely undefined events, eventually leading to cellular apoptosis. TNF-R1 and Fas/APO-1 are trimeric receptors which share extended structural homology, including a cytoplasmic region which has been named 'death domain', as deletions or mutations within it result in the inability by the respective ligands to grigger apoptosis.
Structural similarities both in the extracellular and in the intracellular portion of the two receptors suggest similar mechanisms for the generation of the apoptotic signal, however differences may exist in the complexity of its fine regulation and control, which may be relevant for the specialisation of the death signal in different cell types. Our goal is to define the mechanisms for signal generation and propagation from the two receptors, identifying common central relays as well as unique control features of each apoptotic pathway. We will address receptor structural requirements for productive lingand/receptor interactions, with particular emphasis on the role of alternatively spliced isoforms of the Fas/APO-1 receptor in signal control. Moreover, the function of death domains in the generation of the apoptotic signal will be investigated, specifically by searching for cytosolic death domain-like molecules. Membrane modifications following TNF-R1 and Fas/APO-1 crosslinking and their relevance for the propagation of the death signal will be investigated by measuring different phospholipases and sphingomyelinases activities and identifying relevant downstream targets. We will therefore study how relevant diffusible second messengers can activate potential distal targets, like interleukin-1 converting enzyme (ICE) and homologues, as well as reactive oxygen intermediates (ROI), potentially involved in mediating the effector phase of the response. Finally, the role of bcl-2 family members, key players in the control of the apoptotic response, will be addressed.
Defining the molecular steps responsible for TNF-R1 and Fas/APO-1 induced apoptosis will reveal potential targets for anti-apoptotic strategies adopted by cancer cells to survive. Uncover such strategies has potential relevance for both diagnosis and selective therapy of tumours.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
You need to log in or register to use this function
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Data not available
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
00133 ROMA
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.