Research Projects
Amyloids as Substrate of Biological Functions

Objective and Significance

Amyloids are organised 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.

Research Plan and Methodology

We seek PhD 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.

Professor R Hervás Millán, School of Biomedical Sciences

As a doctoral student at the Cajal Institute and the Autonomous University of Madrid studying biochemistry at the single-molecule level, Rubén Hervás Millán, PhD, was attracted by protein aggregation, and especially functional amyloids, as a biological mechanism to provide gain-of-functions in a time and space-dependent manner. 

Rubén first studied in depth the structural transition from the monomeric, non-amyloid, state to the final amyloid state of CPEB, a synaptic protein synthesis regulator. After finishing his PhD in Spain, Rubén moved to Kausik Si’s lab at the Stowers Institute for Medical Research to tackle a fundamental question in studies of prion-like proteins: what is the atomic structure of a functional amyloid such as CPEB? To address this problem, Rubén developed a multistep purification step and purified Drosophila CPEB from the adult fly head to finally determine the 3D structure of the functional, CPEB amyloid state.

As an independent investigator, Rubén is not afraid of trying new ideas or new experimental venues, attributes that he considers important for pursuing this rather unusual but exciting line of research.

When he’s not in the lab, Rubén enjoys spending time with his wife and friends. He also loves music and concerts, a passion of his since he was a child growing up in Madrid.

Biography
ruhm@hku.hk

For more information or to express interest for this project, please email the supervisor or the specified contact point in the project description.  Interested candidates are advised to enclose with your email:

1. your CV,
2. a brief description of your research interest and experience, and
3. two reference letters (not required for HKUMed UG students seeking MRes[Med]/URIS projects).

Information on the research programme, funding support and admission documentations could be referenced online at the Research Postgraduate Admissions website. General admission enquiries should be directed to rpgmed@hku.hk.

HKUMed MBBS students interested in the Master of Research in Medicine (MRes[Med]) programme may visit the programme website for more information.  

HKUMed UG students interested in the Undergraduate Research Internship Scheme (URIS) may visit the scheme’s website for more information.