The immune system is our body’s major defense mechanism against invading pathogens,
as well as against tumor cells. One of the critical white blood cells that plays a central role in the immune system are T lymphocytes, cells that are generated from blood forming
stem cells through a process that is driven by the Notch signaling pathway. In a number of
clinical cases, for example after radio- and/or chemotherapy prior to stem cell transplantation or in case of HIV infection, patients have reduced T cell numbers, making
them highly susceptible to infections. Providing such patients with more stem cells with
high T-cell potential, or with functionally mature T cells would enhance the recovery of
the immune system and generate new therapeutic breakthroughs. However, in order to
pursue this, we need to expand our knowledge on the molecular mechanisms that control
the development of human stem cells and T lymphocytes and this is the first goal in this
research proposal. Using innovative technologies, we will specifically investigate the role
of the Notch signaling pathway in stem cells and T cell development. Furthermore, since
activating mutations in the Notch pathway result in T-cell tumors, we wish to generate a
human model of this Notch-driven disease in order to understand the molecular
mechanisms that mediate this oncogenic process. This is critical to enhance the
development of to novel therapeutic targets and this is the second goal of this proposal.