Thesis

The effects of proton therapy on protein self-organization: potential benefits for neurodegenerative disorders

• Call:

  ProtoTera Call 2021/1

• Academic Year:

  2021/2022

• Supervisor:

  Daniel Galaviz

• Co-Supervisor:

  Federico Herrera

• Host Institution:

  LIP - Laboratório de Instrumentação e Física Experimental de Partículas

• Granting Degree Institution:

  FCUL (Universidade de Lisboa)

• Typology:

  National

• Abstract:

  Radiotherapy (RT) is commonly associated with the treatment of cancer, where it kills or slows down the growth of tumor cells. In addition, it has also been used to successfully treat amyloidosis [1,2], a superfamily of chronic degenerative disorders caused by deposits of toxic protein aggregates in cells and tissues. Recently, low-dose RT (LDRT) has shown positive results on widespread incurable neurodegenerative disorders such as Alzheimer's disease (AD) or Parkinson's disease (PD) [3,4]. The RT modality has been tested with photons, while proton therapy (PT) has so far not been evaluated. The overall aim of this proposal is to analyze the destructive potential of low-dose proton therapy (LDPT) on the accumulation of toxic protein aggregates associated with these neurodegeneration disorders. Monte Carlo (MC) simulations will be confronted with experiments on purified amyloidogenic protein solutions and live-cell models of neurodegenerative disorders. Current MC algorithms (GEANT4-DNA, TOPAS-NBio and gMicroMC) will be benchmarked and compared in this context. Simulations will be validated by state-of-the-art spectroscopy and microscopy methods both in vitro and on cell models of neurodegenerative disorders, such as AD, PD, Huntington's disease (HD) or Alexander's disease (AxD), all currently available at the host laboratories. The biochemical and biophysical mechanisms underlying the optimal PT conditions for disruption of amyloid deposits will be characterized in close collaboration between LIP/BioISI (FCUL) researchers and the CMAM laboratory (Madrid). The student will thus receive advanced and highly interdisciplinary training in both radiation physics and cell and molecular biology. The results of this multidisciplinary project will lay the groundwork for possible applications of PT on a wide spectrum of neurodegenerative disorders.