Project 1: neurodegeneration
“Autophagic flux and organellar fusion dynamics-predicting cell death in a model of Alzheimer’s Disease”
Autophagy is the degradation process of long-lived proteins, mediated by a unique organelle, the autophagosome. It has been described as the cell’s major adaptive strategy in response to metabolic challenges. A large body of evidence supports that impaired autophagy is implicated in the onset an progression of neurodegeneration. In neuronal tissue an increased autophagic activity has been shown to increase protein clearance and to decrease neurotoxicity. Application is however limited as it is not understood, in which context autophagy is protective or detrimental. This study therefore aims to assess the relationship between autophagic flux and cell death onset in a model of amyloid-induced neuronal toxicity. A neuronal cell line will be employed and assessed for autophagic flux, mitochondrial network- and fission/fusion as well as metabolic parameters. Cells will then be exposed to injury, while the onset of apoptosis and necrosis is monitored. The % magnitude of change in autophagic flux will be modulated and its resulting effect on the degree of protection assessed.
Project 2: cancer
“The preventative abilities of a ketogenic diet and intermittent fasting in relationship to the
carcinogenesis of astrocytoma”
Astrocytomas are a malignancy with particular poor prognosis, due to the often aggressive and infiltrative growth pattern observed. Astrocytomas respond poorly to chemotherapy and radiation, and due to its network-like proliferation, it is rarely accessible to surgery. The recent advances in our understanding of cancer metabolism indicates that protein degradation through autophagy is crucial to maintain the high metabolic demand of cancer. It has been shown that modulation of autophagic activity has a robust effect on cancer proliferation, due its potential of inducing metabolic failure. In addition, the role of autophagy in reducing and limiting genome damage, has recently been revealed. These are crucial parameters that influence carcinogenic properties. Many selected clinical trials are currently being performed that utilize the modulation of autophagy in order to improve treatment regimen, with promising results. It is known that dietary intervention, such as a ketogenic diet, as well as short term nutrient deprivation both upregulate autophagic flux in the brain. This intervention has historically been reverted to due to its powerful anticonvulsant and antipeileptogenic properties. However, it remains largely unknown whether a combination of such intervention also reduces carcinogenesis in brain tumors. The aim of this study is hence to dissect the relationship between dietary intervention through a change in generic substrate provision (from glucose to ketone bodies) as a background substrate, concomitantly with an intermittent induction of neuronal protein clearance brought about by short term nutrient deprivation and their overall effect on carcinogenesis. A unique in vitro and ex vivo approach will be utilized to address the research question most optimally, in combination with powerful analytical techniques that assess and quantify carcinogenetic properties and autophagy.
If interested, please send you CV to:
Dr Ben Loos, firstname.lastname@example.org
Department of Physiological Sciences, Stellenbosch University, South Africa