An integrated engineering-computational-biological approach to unravel molecular dysfunction in Parkinson’s disease

In this cross campus proposal, our ultimate goal is to develop a human relevant in vitro platform for studying Parkinson's disease (PD), and to use it for identifying PD-associated abnormal pathways using patient specific differentiated cells.

Prof. Roded Sharan, Prof. Uri Ashery & Prof. Ben Maoz

Department of Biomedical Engineering; Sagol School of Neuroscience; Blavatnik School of Computer Science; School of Neurobiology, Biochemistry and Biophysics; Tel Aviv, Israel TAU

Prof. Roded Sharan
Prof. Rodad Sharan is a full professor in the Department of Computer Science, Tel Aviv University. He did his doctoral studies in the Department of Computer Science at Tel Aviv University and his post-doctoral studies at the University of California, Berkeley. Today he heads a research group specializing in the analysis of biological networks and their applications to medicine.
Prof. Sharan has published over a hundred scientific articles in bioinformatics and graph theory. His current research focuses on using networks to decipher disease mechanisms and predict drug properties

Prof. Uri Ashery-
Graduated from the Hebrew University of Jerusalem, I was always fascinated by the mechanism of neuronal function. Specifically I am interested in understanding synaptic plasticity in normal and disease states. Our lab uses multidisciplinary approaches combining electrophysiology, super-resolution and TIRF microscopy, molecular and cellular neurobiology and computer modeling, to study synaptic plasticity and correlate between molecular changes, synaptic function and dysfunction and animal behavior.

Prof. Ben M. Maoz -
Prof. Maoz is a faculty member at the Sagol School of Neuroscience and the Department of Biomedical Engineering at Tel Aviv University. Dr. Maoz did his Ph.D on nano-optics in the School of Chemistry at Tel Aviv. During his post-doctoral studies, at Harvard University, in Prof. Don Ingber and Kit Parker, he developed Organ-on-a-Chip platforms for studying human relevant physiology.

In this cross-campus proposal, we set out to develop a human-relevant in vitro platform for studying Parkinson’s disease (PD), and to use it for identifying PD-associated abnormal pathways using patient-specific differentiated cells.

Over the first six months, we developed the computational, biological, and engineering infrastructure for tackling this goal, advancing considerably on all fronts.
On the computational side, (Sharan Lab) we developed a tool for pathway enrichment analysis that is based on projecting the raw activity data of disease vs. healthy proteins on a network of protein-protein interactions and then smoothing this information using network propagation techniques. In order to validate and assess the model, we did a massive literature survey to identify specific genes that were identified and published previously (in databases). It is important to note that the next step will be to apply this on the in-house data that will be available from our organoids and iPSC. The data we found was based on the expression data of iPSC-derived dopaminergic neurons from LRRK2-G2019S mutants vs. healthy controls from Carola et al., Nature 2021.
Our initial analysis identified four significantly enriched pathways (circled in bold out of top 100, see figure below) known to be associated with PD. As can be also observed, network propagation yields more significant results than the raw fold-change scores, demonstrating the power of analyzing expression data in the context of a network.

 

To read more Press here: Research plan

 

 

 

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