Richard Callaghan - Overview
The general focus of research in our laboratory is
to facilitate pharmacological intervention in disease. More specifically,
our main endeavour is to overcome the significant clinical problem of
resistance to chemotherapy in cancer. The resistance may be either inherent
or develop during treatment with anti-cancer drugs. Other areas of research
include (i) characterisation of the ability of oestrogen, and its derivatives,
to maintain low blood pressure via a "non-genomic" pathway and
(ii) elucidation of molecular mechanisms underlying visual disorders such
as Stargardt disease and age-related macular dystrophy. The investigations
in our laboratory rely on strong interaction between biochemical and structural
aspects of proteins involved in mediating drug action.
Visual Impairment
Mutations in the gene coding for the ABCR transporter
protein are associated with a number of diseases linked to impaired visual
pathways. There is scant information regarding the role of this protein
in normal visual pathways, however transport of retinal derivatives appears
likely. Our research is aimed at identifying the molecular species that
ABCR interacts with, and translocates across the disc membrane in rod
cells of the retina.
Hypertension
The calcium and voltage gated, high conductance potassium
channel (maxi-K) plays a central role in restoring the resting potential
of excitable cells. This action in smooth muscle cells is important in
setting vascular tone; consequently pharmacological manipulation of maxi-K
channels remains a potential route for management of hypertension. We
are investigating the structural organisation of pore-forming and regulatory
proteins in the channel complex. This information will help to characterise
the route by which oestrogen derivatives can regulate blood pressure via
a "non-genomic" pathway mediated by maxi-K channels.
Resistance to Chemotherapy
The efficacy of chemotherapy is severely compromised
in many different cancer types due to the emergence of resistance pathways.
The apparently non-specific drug efflux pump P-glycoprotein mediates one
of the major clinically relevant pathways. Our long-standing investigations
have provided insight into the molecular mechanisms underlying the poly-specific
and partially coupled transport process mediated by this protein. We are
continuing to develop and characterise high potency inhibitors of the
protein in conjunction with industrial partners. Many of these agents
are benefiting our efforts to elucidate the mechanism of transport by
P-gp through characterisation of how drug-binding events couple with energy
production within the protein. In collaboration with Dr Mark Rosenberg
we are progressing with the goal of describing the structure of P-gp by
cryo-electron microscopy of 2-D crystals and monitoring how the structure
alters during the transport process. A further molecular based goal is
to discover the location of regions in P-gp that are involved in drug
binding/recognition and those mediating communication between domains
in the protein. However, there appears to be no single route for generating
resistance to chemotherapy in tumours. Consequently, we are also probing
the interaction between the different pathways causing resistance by altering
drug pharmacokinetics, such as metabolism, efflux and permeation through
solid tumour masses. In addition, we are examining the reduced efficacy
of anti-cancer agents to produce ceramide-induced apoptosis. The modulated
pharmacokinetic properties and ceramide-induced apoptosis are being investigated
in 3-dimensional in vitro models of solid tumour architecture. A detailed
understanding of drug kinetics in this "hostile" environment
will allow us to better design chemotherapeutic approaches to treat cancer.
