Taming the Hippo – revealing fundamental insights into the cellular aging process

Supervisors: Dr Carsten Gram Hansen, Dr Paul Andrews, Professor Andrew Hopkins

Project description:

The general population is aging and to improve life-quality during the full life-course, a fundamental understanding of the underlying mechanism that controls normal physiology and homeostasis across the lifespan is needed. So far how this is achieved and regulated at the cellular level is poorly understood.

Importantly, the Hippo pathway has recently been identified as a central cell-signalling pathway that regulates organ size and cellular homeostasis (1,2). The Hippo pathway is notably regulated by both mechano-transductive, hormonal and nutritional inputs (1,2). All inputs that dramatically changes during the human lifespan.

Importantly, fundamental questions of how this pathway is regulated to obtain a strict and temporal regulation in a variety of cell types and in different organs across the lifespan have so far not been answered (1,2).

This project takes advantage of a large successful screening effort that is currently taking place to identify modulators of the Hippo pathway. This project is a unique partnership between the pharmaceutical industry and academia via the National Phenotypic Screening Centre (NPSC). Dr Hansen is the academic lead, and this collaboration has to date unveiled its first series of exciting novel hits. The student will interrogate how these small molecules function, with emphasis on the mode of action, the effect on the temporal subcellular localisation of the Hippo Pathway components, and the small molecules efficiency in a variety of different cell types (both stem cells and a range of differentiated cell types). This project will generate new molecular insights into the regulation of the Hippo pathway, how this regulation is deteriorated in aging cells and thereby also into the cellular basis of why organisms age. Importantly, this might reveal insights into how the regenerative potential in a temporal manner can be safely boosted in aged organs (3).

Training outcomes

The student will be trained in a range of diverse skill sets at the interface between biomedical, robotics and computational systems. The student will have access to expertise and large scale screening facilities with chemistry support available at NPSC in Dundee. The student will also carry out live cell fluorescent imaging, genome editing, culturing of primary and stem cells, transcriptomics and a range of biochemical assays in Edinburgh. The student will therefore both be trained in interdisciplinary and quantitative skill sets, which will ensure the student becomes an agile T-shaped researcher.

We seek a highly motivated, enthusiastic and team-oriented student for this timely, challenging and interdisciplinary project.

References:

1.            Hansen, C.G., Moroishi, T. & Guan, K.L. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol 25, 499-513 (2015).

2.            Moya, I.M. & Halder, G. The Hippo pathway in cellular reprogramming and regeneration of different organs. Curr Opin Cell Biol. Dec; 43:62-68 (2016).

3.          Taguchi, J. & Yamada Y. In vivo reprogramming for tissue regeneration and organismal rejuvenation. Curr Opin Genet Dev. Aug 2; 46:132-140 (2017).

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