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Digital archive of theses discussed at the University of Pisa


Thesis etd-02252014-171653

Thesis type
Tesi di dottorato di ricerca
Thesis title
Adenosine receptor ligands and Angiogenin in cell proliferation/differentiation processes
Academic discipline
Course of study
tutor Prof. Martini, Claudia
  • Adenosine receptor
  • Allosteric modulator
  • Angiogenin
  • copper
  • osteoblast
Graduation session start date
Proliferation and differentiation processes have been widely studied during the past decade. The idea that growth is poorly compatible with differentiation has been accepted, and the mechanisms underlying proliferation/differentiation switches are still unclear. Though, diverse proteins and intracellular signals have been emerged as regulator of this switch in several cell types. The stem cells are the only cell type able to differentiate and proliferate during lifetime.
The ratio of proliferation/differentiation varies depending on the cell-type, however the balance of these processes is fundamental to maintain the tissue homeostasis. An excess of self-renewal may lead to tissue hyperplasia and/or cancer, conversely an excess of differentiation may lead to tissue degeneration and/ or tissue aging. The balance between these processes is tightly regulated by several transcription factor, receptor and signals molecules. The switch from proliferation to differentiation depends on both an inhibition of proliferation and the activation of the differentiation-specific genes that are characteristic of each cell types. However, to date the exact mechanisms for this switch from proliferation to differentiation and viceversa is largely unknown.
Recently the importance of adenosine receptor, and in particular of A2BAR has been pointed out. The A2BAR activation has been involved in the induction of differentiation in different cell type (e.g. mesenchymal stem cells; human lung fibroblasts). Moreover the A2BAR has been proved to play a role in proliferation of endothelial cells and coronary artery smooth muscle cells.
Angiogenin is a soluble protein physiologically present in blood plasma regarded as one of the most potent angiogenic factor. Angiogenin has been proved to be essential in endothelial cell differentiation as well as in the growth of neuritis. Moreover Angiogenin is an important regulator of cell proliferation both in physiological condition than in pathological one.
Considering the A2BAR and Angiogenin role in diverse processes of proliferation/differentiation, the aim of the present work was to clarify the molecular mechanism underlying the processes of osteoblastogenesis and angiogenesis, as well as to discover new potential targets for several pathologies.
A new series of allosteric modulator of A2BAR are discovered and characterized. Furthermore the ability of this compounds to induce and promote osteoblastogenesis is evidenced. Then, the feature and the role of copper binding on angiogenin are evaluated. Copper is able to modulate the angiogenic activity of Angiogenin as well as its nuclear activity and transcription. Taken together these results could be used to applicable in regenerative medicine. The synthetic compound could promote the differentiation of osteoblast, as well as angiogenin could modulate the proliferation and differentiation of endothelial cells promoting angiogenesis.