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Cell Biology: Exploring the mitotic functions of ASPM in human brain size regulation


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Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Dr Jacquelyn Bond and Professor Michelle Peckham
Additional supervisors
Dr J Bond, Dr EE Morrison, Professor M Peckham
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

The increase in relative brain size is one of the most striking events in human evolution. To determine how human brain size is normally regulated we have investigated the cause of autosomal recessive primary microcephaly (MCPH), a congenital disorder of reduced brain size and associated mental retardation. MCPH is a disorder of reduced neural progenitor cell and neuronal cell number in the developing brain. <br /> <br />

<h2 class="heading hide-accessible">Full description</h2>

<p>Homozygous mutations in the Abnormal Spindle-Microtubule Assembly gene (ASPM &ndash; previously named Abnormal Spindle -like Microcephaly associated gene) are the most common cause of MCPH1. ASPM is a 410kDa microtubule associated protein which localises to the spindle poles during mitosis and to the midbody during cytokinesis2-3. Analysis of patient cells containing ASPM mutations and cell lines in which ASPM has been reduced using siRNA have identified a number of mitotic functions for ASPM. Notably, interactions involving the C-terminus of ASPM are involved in the final stages of cytokinesis. We wish to further investigate the protein pathways involved in this.&nbsp;</p> <p>Using cell-based siRNA library screening, Yeast-two hybrid and other interaction studies, we have identified a number of ASPM interacting proteins that we hypothesize to be involved in spindle orientation, cytokinesis, cytoskeletal organisation, structural changes in ASPM and the regulation of ASPM activity. This PhD project will validate and further study a number of these protein interactions.<br /> &nbsp;&nbsp;<br /> The project will utilise a range of biochemical, molecular biological and cell biological techniques. Gain or loss-of-function cellular phenotypes will be assessed by over-expression and siRNA-mediated knockdown of gene expression in cultured cells, alongside analysis in a unique resource of MCPH patient primary cells. Live cell imaging, confocal microscopy, super resolution microscopy and high throughput imaging will complement these approaches. The programme of work will provide a motivated and enthusiastic post-graduate student with an excellent foundation in research training in a range of modern techniques including PCR, cloning, co-immunprecipitation, GST fusion pull down assays, siRNA gene knockdown, cell culture, RNA extraction, Real time PCR, immunofluorescence staining, Western blotting and cellular imaging of fixed and live cells.</p> <h3 style="margin-left: 2.85pt;">References:</h3> <ul> <li style="margin-left: 2.85pt;">Bond et al., 2003, Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Human Genet. 73:1170-1177</li> <li style="margin-left: 2.85pt;">Bond et al., ASPM is a major determinant of cerebral cortical size. 2002, Nat Genet. 32:316-20</li> <li style="margin-left: 2.85pt;">Higgins et al., Human ASPM participants in spindle organisation, spindle orientation and cytokinesis. 2010 BMC Cell Biol. 11:85-101</li> </ul> <p style="margin-left: 2.85pt;"><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="">online application form</a> and attach the following documentation to support your application.&nbsp;</p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme&rsquo;s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medical Research as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: &bull; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &bull; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School e: <a href=""></a></p>

<h3 class="heading heading--sm">Linked research areas</h3>