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Title: College of Life Sciences and Medicine


1
Postgraduate Research
BONE Research Theme
Aberdeen Oliver Bird Collaborative Centre
Rheumatism Research Programme
MORE PROJECTS FOR PhDs STARTING IN 2004
Responses of bone cells to shear forces. Fluid
flow through bone canaliculi has been suggested
as major regulatory factor in the response of
bone to mechanical signalling. In vitro, shear is
generally applied by pumping culture medium over
cells, osteoblasts or osteocytes, in a flow cell.
We have recently obtained two complementary
devices for applying shear forces to cells in
vitro. One is a microscope-mounted
temperature-controlled shear cell in which
individual cells can be observed whilst subjected
to carefully controlled shear conditions. The
second one is a small-scale flow device in which
larger numbers of cells can be manipulated,
again, whilst being observed through a
microscope. A time-lapse imaging programme is
available to perform live-cell imaging of the
cells during flow. This project will use these
devices to apply controlled shear forces to bone
cells, transfected with a variety of reporter and
expression constructs, and monitor their
responses using fluorescent protein technology.
Of specific interest are cytoskeletal
(re)organisation and the responses of NO
synthases, including production of NO itself.
Gene arrays technology will be used to identify
the main signalling pathways activated by
exposure to fluid shear stress in bone cells.
Comparison may also be made with direct loading
of bone explants in culture over short time
periods, studies for which equipment is already
available. By doing so the relative importance of
direct loading (strain) versus shear stress in
the mechanical regulation of bone can be
explored. This project will provide a strong
background in cell biology and live cell imaging
using fluorescent protein technology.  Main
Supervisor Prof Richard M. Aspden
(r.aspden_at_abdn.ac.uk) Other Supervisor Dr Miep
Helfrich
The University of Aberdeen have been awarded more
than 540,000, creating an outstanding
opportunity for five highly talented young PhD
students to receive advanced scientific training
in rheumatic disease research as from 2003. The
University is one of only five UK centres to
receive this prestigious award from the Oliver
Bird rheumatism programme supported by the
Nuffield Foundation.
The Aberdeen Oliver Bird Collaborative Centre
will be focussed around a new research theme
specifically targeted at Musculoskeletal (Bone)
Research (MSR) within the University of
Aberdeens Institute of Medical Sciences (IMS).
The theme brings together a highly successful
internationally-recognised group of researchers
spanning the entire field of musculoskeletal
disease with an emphasis of the effects of
disease on the biology of bone. The excellence of
the group was recognised in the 2001 RAE by the
award of 5 rating.
PROJECTS ON OFFER FOR PhDs STARTING IN 2004
Pharmacogenetics of Bisphosphonates
Bisphosphonates are currently the most important
class of drugs used in the treatment of bone
diseases such as osteoporosis, Pagets disease
and cancerous bone disease. These drugs exert
their effect on bone cells by inhibiting the
enzyme FPP synthase, leading to apoptosis of
bone-destroying osteoclasts. Bisphosphonates have
shown to reduce fracture rates in most patients
suffering from osteoporosis. However, some
patients respond poorly to these drugs and others
develop adverse drug reactions such as flu like
symptoms. We will use state-of-the art
techniques to explore the possibility that some
patients respond poorly to bisphosphonates or
develop adverse effects because of polymorphisms
(minor changes in DNA sequence) in particular
genes. The project will provide a strong
background in molecular genetics techniques such
as DNA sequencing, gene cloning, mutation
detection and analysis, bio-informatics and cell
culture.  Main Supervisor Dr O Albagha
(omar.al_at_abdn.ac.uk) Other Potential Supervisors
Prof MJ Rogers, Prof SH Ralston, Prof DM Reid
A post-genomic bioinformatic and transgenic
analysis of polymorphisms within putative
transcriptional regulatory regions of the
Estrogen Receptor Alpha gene. Various
polymorphisms have been defined around the
Estrogen receptor alpha (ESR1) gene locus that
many studies have associated with increased
susceptibility to reduced bone density
(osteoporosis) and fracture of the lumbar
vertebrae. Many of these polymorphisms may occur
in regions that are responsible for correctly
mediating ESR1 transcriptional regulation and may
be able to disrupt the normal functioning of
these elements resulting in a mis-regulation of
ESR1 and disease symptoms relating to aberrant
bone deposition in later life. The project will
be based on a post-genomic bio-informatic study
of non-coding regions surrounding ESR1 to
determine whether any of the polymorphisms linked
to disease susceptibility occur with regions of
high conservation between mouse, human, rat and
pufferfish. We will isolate these regions and
carry out a series of in vitro (cell based) and
in vivo (transgenic) studies to test the
transcriptional properties of these putative
regulatory elements. Using a combination of
techniques we hope to mechanistically link the
occurrence of ESR1 polymorphisms through
transcriptional mis-regulation to disease
susceptibility.  Main Supervisor Dr A MacKenzie
(alasdair.mackenzie_at_abdn.ac.uk) Other
Supervisors Prof Stuart Ralston
(s.ralston_at_abdn.ac.uk)
Role of GTPases in osteoclast function.
Osteoclasts are the cells responsible for
physiological and pathological bone resorption.
Prof Mike Rogers group have recently
demonstrated that small GTPase signalling
proteins are fundamental to the function and
survival of osteoclasts, since bisphosphonate
drugs (pharmacological inhibitors of bone
resorption) act by preventing the prenylation
(lipid modification) of these proteins. Little is
known about the expression and function of small
GTPases in osteoclasts, but Rogers group have
recently found that Rap1A and Rap1B are highly
abundant in osteoclasts and probably play an
important role in inside-out signalling via
integrins such as avb3. Rap1 proteins may also
control the effect of fluid flow and shear stress
on osteocytes, thereby affecting the response of
the skeleton to mechanical loading. This project
will investigate the role of Rap1 in osteoclasts
and osteocytes by generating transgenic mice
expressing RalGDS-RBD (a dominant negative
inhibitor of Rap1A/Rap1B signalling) via an
osteoclast- or osteocyte-specific promoter (TRAP
or DMP-1 respectively). This will allow
characterisation in vivo of the role of Rap1 in
normal bone cell physiology and in responses to
mechanical/pathological stimuli. Main
Supervisor Prof Mike Rogers (m.j.rogers_at_abdn.ac.u
k) Other Supervisor Dr Sanbing Shen
Endocannabinoid regulation of bone remodelling.
Recent studies have demonstrated the importance
of neurogenic influences on the regulation of
bone mass. Of particular interest has been the
realisation that leptin regulates bone formation
and bone mass through a hypothalamic relay.
Recent studies have demonstrated that cannabinoid
receptor 1 (CB1) knockout mice have abnormalities
of bone mass. Since leptin is a potent stimulator
of cannabinoid release in the CNS, this raises
the possibility that endocannabinoids are
involved in the regulation of bone mass. This
will be investigated by studying the effects of
cannabinoid receptor ligands on bone mass and
bone loss in mice with leptin deficiency (ob/ob)
and deficiency of leptin receptors (db/db) and by
studying bone metabolism in mice with targeted
activation of CB1, CB2 and CB1/CB2 cannabinoid
receptors. This work is potentially important
from a clinical view point in opening up the
possibility that the endocannabinoid system may
be a hitherto unrecognised regulator of bone
remodelling, Main Supervisor Prof Stuart Ralston
(s.ralston_at_abdn.ac.uk) Other Supervisor Dr Ruth
Ross
Other possible projects are available accompanied
by a comprehensive support and education package
and a generous stipend. For details of
application procedure see our accompanying
POSTGRADUATE SUPPORT Poster
College of Life Sciences and Medicine
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