Download FST 12 Endoplasmic Reticulum Stress in Human Diseases

Project title: Endoplasmic Reticulum Stress in Human Diseases: Functional Link with Mitochondria
Studentship Code: FST12
Cell organelles, endoplasmic reticulum (ER) and mitochondria play an important role in the maintenance of
cellular homeostasis and dysfunction of either or both have been implicated in many human diseases,
including cancer, diabetes, cardiovascular, neurodegeneration and ischemia. The ER is the primary site for
synthesis and folding of secreted and membrane-bound proteins and the central site for Ca2+ storage.
When the ER homeostasis is perturbed due to pathophysiological conditions such as high protein demand,
hypoxia, viral infections and other stimuli it results into accumulation of misfolded and unfolded proteins in
the ER lumen, a condition termed as ER stress (ERS). To maintain homeostasis, ERS activates an
unfolded protein response (UPR). Three main proteins mainly initiate the UPR: IRE1α, PERK and ATF6.
Over-activation of UPR could trigger changes in mitochondrial function and eventually, cell death.
Mitochondria are cell organelles that create energy to run the cell. Mitochondrion regularly divides (fission)
and fuses (fusion) to maintain the shape, size, and number, in addition to changes in the morphology and
this process is termed as mitochondrial dynamics. A growing body of evidence now supports a role for ER–
mitochondria interactions. Our recent studies in human adipocytes have shown that the mitochondrial
dynamics and function are regulated by UPR but the actual mechanism is not fully understood. A better
understanding of the complexity of the ERS and the UPR on mitochondrial dynamics and function could
lead to novel therapeutic approaches for a range of disease states. Therefore, the aims of the project are to:
Aim 1: To investigate the effect of ERS on mitochondrial dynamics and function:
Method: ERS will be induced in a cell culture model by treating cells with ERS inducers and the
components of mitochondrial dynamics will be studied.
Aim 2: To investigate the effect of specific UPR pathways on mitochondrial dynamics and function.
Method: Either each of the UPR pathways will be inhibited individually chemically or by RNA interference
after ERS induction and the components of mitochondrial dynamics studied.
Aim 3: Computational modelling of the ER-Mitochondria cross-talk (with computer sciences)
All the above studies will be carried out in human preadipocyte cell line Chub-S7 and other mammalian cell
lines such as HepG2 and Min6.
Student Training: The student will take part in the University Graduate School and Faculty Doctoral
Research Development Programmes. In addition to the subject specific skills listed above, the student will
also gain important transferable skills (e.g. presentation skills, scientific writing and employability skills).
The student will be encouraged to join learned societies (e.g. British Endocrine Society, Biochemical
Society, American Diabetes Association), which provide excellent support in further training via workshops
and networking and research dissemination via conferences.
Related publications
[1] Adaikalakoteswari A, et al. (2015) Clinical Epigenetics. 7(1):14.
[2] Jackisch L. et al. (2016) Endocrine Abstracts (2016) 44 P193; DOI:10.1530/endoabs.44.P193
[3] Lucia Martinez de la Escalera et al. (2017). BMC Medicine (accepted)
[4] Schisano B, et al. (2012) Regul Pept. 174(1-3):46-52.
[5] Alhusaini S. et al. (2010) Biochem Biophys Res Comm. 397(3):472-478
Contact
Informal project enquiries to Prof Gyan Tripathi ([email protected]) and general enquiries to Dr
Stephen Getting ([email protected]) or Professor Taj Keshavarz
([email protected]).
Apply now
Applications should be made to the Anatomy, Physiology & Pathology MPhil/PhD programme and you
should clearly state that Studentship Title and code (i.e. FST12) on your application.
For details on how to apply
https://www.westminster.ac.uk/courses/research-degrees/research-areas/life-sciences/how-to-apply