Replacing the fuzzy with the hard:
Quantitative interrogation of Drosophila eye phenotype in the context of Alzheimer's Disease.
John Aston (Statistics) and Bruno Frenguelli & Kevin Moffat (Biological Sciences)
Model organisms such as the fruit fly Drosophila melanogaster provide valuable insight into human
biological processes: they have well understood genetics allowing manipulations impossible or very
difficult in mammalian species; they have a rapid life-cycle that permits the influence of genetic
manipulations to be observed rapidly, and they have stereotypical behaviours (eg courtship, feeding) and
morphology (eg eye shape) which can be investigated to examine the influence of genetic modifications.
A further advantage is that human genes can be inserted into the fruit fly to examine the consequences of
protein-protein interactions thought to be responsible for human diseases.
One such protein-protein interaction is between human
protein kinases and tau, a protein responsible for one
hallmark of Alzheimer's Disease - the neurofibrillary tangle.
These tangles accumulate inside brain nerve cells and result
in their destruction. Understanding how this accumulation
occurs is an important goal in Alzheimer's research and may
provide means by which to prevent, or even reverse, tangle
formation.
We have been studying the effects of expressing human tau
selectively in the Drosophila eye (Figure 1), an organ that
has a regular and practically immutable appearance under
normal circumstances. When we express tau we observe a
disordered appearance when compared to the normal eye.
Traditionally, Drosophila neurobiologists have applied
qualitative and subjective assessments of such phenotypes either the eye is "worse" or "better" - clearly not an ideal
situation, especially when eye (or other morphological)
phenotypes are subtle. Furthermore, this approach makes it
very difficult to assess whether two interactions are merely
additive or multiplicative.
Fig 1. Scanning electron micrographs of
Drosophila eye showing A) control eye, B)
eye overexpressing human BRSK, a tau
kinase, showing "little" disorder, C) "more"
disorder caused by expression of human tau,
D) "worse" appearance caused by combined
expression of human tau and human BRSK.
We plan to create quantitative descriptions of the appearance of the Drosophila eye in order to make
rigorous and statistically robust assessments of the influence of genetic manipulations. This will be
achieved by implementing techniques from statistical stereology and stochastic geometry. This will have
the benefit of removing subjectivity from the traditional assessment and provide more insight into the
nature of the underlying biology.
The primary aim of the project will be to develop methods to test the effects of expression of Tau and
BRSK statistically in order to provide quantitative assessment of the distortion in the geometry. This will
involve the implementation of computational techniques for data sets comprising of images. Training can
be gained on both the production of SEM images and the current analysis of these images.
This project requires the student to have familiarity with probability and also be happy to undertake
computing in environments such as MATLAB. The project itself does have the possibility of leading to a
PhD where the image assessment can be extended to incorporate more advanced stochastic techniques
and work undertaken in the underlying theory needed for the assessment.