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Deciphering SENsing Of membrane satuRation with functional genetics (SENSOR)

Periodic Reporting for period 1 - SENSOR (Deciphering SENsing Of membrane satuRation with functional genetics (SENSOR))

Reporting period: 2021-09-01 to 2023-08-31

Fatty acids (aka fats) are essential building blocks of membranes in each cell in our body, and dysregulation of their metabolism is associated with a wide-range of human conditions, including cancer, cardiovascular, neurodegenerative, and liver disease. For example, dysregulated fat production in the liver results in fatty-liver disease and inflammation that may lead to development of liver cancer. Related to this, cancer cells increase their fat synthesis to promote their uncontrolled growth, making this process an attractive anti-cancer target. Fats come in different sizes and shapes. A major way to distinguish fats is their saturation (i.e. saturated vs unsaturated fats), which is an intrinsic chemical feature that determines many properties of the cell membranes in which fats are incorporated into. Like fat synthesis, fat saturation is altered in many diseases, and for example elevated membrane saturation of cancer cells is associated with resistance to chemotherapy and increased metastatic spreading. In fact, there is even an enigmatic link between fat synthesis and saturation, with each one reciprocally influencing the other. Remarkably, despite the importance of controlling fat saturation in membranes, the fundamental mechanism(s) that sense and respond to changes in membrane saturation are unknown. In SENSOR we propose for the first time to directly address this issue using innovative genetic and cellular systems.
To uncover the mechanisms and genes that sense and regulate fat saturation in human cells one must devise an approach that can report on fat saturation in living cells. Yet as analytical assays to measure fat saturation require dissolving the cells and extracting their fats, measuring saturation in living cells is an unsurmountable challenge that has largely prevented addressing this fundamental question. In SENSOR we have a solution to this problem. This solution is based on the use of engineered human cells together with a genetic approach that will allow us to test and identify which genes in the human genome are involved in regulating fat saturation.
Project SENSOR has achieved a major goal - we developed a green fluorescent reporter, which can sense saturation of fats in the living cells. This reporter has been further used to identify which genes in human cells are regulating and sensing fat saturation. Additionally, such fluorescent reporter can and will be applied to find alternative treatments for fat metabolism related diseases, such as Adrenoleukodystrophy and Zellweger syndrome.
We successfully established a fluorescence based saturation reporter in live mammalian cell lines and our experiments demonstrated that this reporter was sensitive to addition of external fats (saturated and unsaturated fatty acids). When saturated fatty acids were added the fluorescence signal from this reporter increased in living cells, and vice versa - in cells exposed to unsaturated fats, the fluorescence signal was reduced. Using these saturation reporter cells we conducted a genetic experiment in which we could test the effect of each gene in our genome on the reporter signal (so called whole-genome genetic screen). The genetic screen was done and we are currently investigating the results.

The results of the project have been presented in international (for example European Lipoprotein Club) and local conferences (Rembrandt Symposium) in oral and poster form, and throughout informal discussions with experts in the field.
Given the fundamental nature of SENSOR, the primary beneficiary will be the scientific community, and in particular scientists working in the field of FA metabolism and its relation to human disease, and those employing whole-genome genetic approaches in their studies. Since the degree and nature of FA saturation will influence each cell in the body, the fundamental findings we make will be important to the broad scientific community, including to scientists studying liver, cardiovascular, cancer, diabetes, and neurodegenerative disorders. While not the primary goal of SENSOR, our findings may in the long run also benefit the clinical setting through the development of diagnostic and therapeutic venues in FA-related human diseases.
Cells expressing saturation reporter
Dissemination of results in a scientific meeting