Amyloids as Substrate of Biological Functions

Amyloids are organized cross β-sheet-rich protein aggregates associated with pathological conditions, including Alzheimer’s disease. However, self-replicating amyloid states also operate in diverse biological phenomena. Indeed, given that amyloids are broadly distributed across multiple phyla, they may form part of an evolutionarily conserved mechanism serving specific physiological functions. Although our understanding of the principles that govern pathological protein aggregation is increasing, how amyloids could be functional, regulatory entities is unclear. This is due, in part, to the lack of high-resolution structural information of functional amyloids. In this project, we will explore the structure and function of amyloids, obtained from native environments, implicated in key biological processes such as human memory consolidation and animal development. Coupling state of the art cryo-EM with orthogonal data, such as activity tests or animal models, we will test the biological consequences of amyloid formation and disruption in memory persistence and embryonic development. The results derived from this project will provide insight into how a transient stimulus creates a persistent change in physiology in a tissue/context-dependent manner. In addition, the findings derived from this project may force us to rethink why and how other amyloids are harmful, particularly to the nervous system, and how protein aggregation-based diseases, such as Alzheimer´s, might be treated in the future.

We seek two Ph.D. students to join our lab. Basic experience in structural biology, particularly cryo-EM, and/or cell biology and animal models is valuable, although not mandatory. Projects will involve processing of biological samples such as human brain or Drosophila embryos, protein isolation, sample preparation and high-resolution cryo-EM data acquisition, computer-based single-particle reconstruction, and de novo generation of atomic models, in combination with cell biology, super resolution imaging, and animal model generation (i.e. mice and Drosophila) to test the consequences, on the underlying biological processes, of amyloid disruption in vivo.

Faculty information, funding opportunities and application deadlines: https://www.findaphd.com/phds/program/biomedical-research-hku-li-ka-shing-faculty-of-medicine/?i586p4119