Pleasantine Mill Research Group

Section: Disease Models

Research in a Nutshell 

Cilia are specialized microtubule-based structures found on the surface of most mammalian cells. They play key sensory and sometime motile functions. When cilia go wrong, either through defects in their assembly or function, they can have devastating effects on human development (birth defects) or postnatal health, where cilia dysfunction underlies blindness, kidney failure and infertility. This broad group of genetic disorders is termed ciliopathies.  We know that hundreds, if not thousands of genes are involved in building and maintaining this highly conserved organelle. But for the most part, we know very little about which and how individual genes are required for specific ciliary functions. 

My lab uses the power of genetics combined with the latest molecular and cellular biology tools to address the following questions: How do we build the basic blueprint required for core cilia function? How is this basic genetic program elaborated on for specific ciliary functions, like ciliary motility? What can we learn about cilia gene function from human disease alleles? 

There are four areas of interest in our lab: 

1.  Evolutionary genetics In collaboration with Prof. Andrew Jarman (Centre for Integrative Physiology, University of Edinburgh), we use the power of genetics to identify potential cilial disease candidates in the relatively simple fruit-fly model to guide our mammalian studies, done mostly in mice. 

2. Genetic screens We have carried out phenotype-driven forward genetics (ENU mutagenesis) screens and reverse genetics (candidate siRNA) high-content cell-based screens to dissect the functional complexity of cilia. 

3. Human disease genetics We work closely our clinical genetics collaborators to identify and characterize human ciliopathy alleles. We use the CRISPR/CAS9 system of gene editing to build better models of human disease candidates to correlate genotype with cellular phenotype and overall health. We examine the effects of these mutations integrating microscopy, transcriptomics and proteomics. Taken together, we hope to develop evidence-based strategies for clinical management of ciliopathies, and perhaps even a cure.

4. Super-resolution and live imaging Primary cilia are small, dynamic structures whose imaging is very much limited by these characteristics in terms of time and resolution. We aim to build tools to better capture events on a finer-scale across time and space using confocal, super-resolution (SIM, SPIM, PALM) and electron microscopy.

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