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UCL Division of Biosciences Examples of Research that can be Translated from Basic Biology to Clinical Problems. Collated by Maria Fitzgerald Biosciences Translational Coordinator. Summary. Diabetic Neuropathy – Lincoln, CDB Bone Disease – Arnett, CDB

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slide1

UCL Division of Biosciences Examples of Research that can be Translated from Basic Biology to Clinical Problems

Collated by Maria Fitzgerald

Biosciences Translational Coordinator

summary
Summary
  • Diabetic Neuropathy – Lincoln, CDB
  • Bone Disease – Arnett, CDB
  • Pulmonary Hypertension and Myocardial infarction – Hobbs NPP,
  • Nerve repair & demyelinating disease – Jessen, CDB
  • Antibody Directed Enzyme Drug Therapy – Taylorson, SMB
  • Spectroscopy for diagnostics – Rich, SMB
  • Steroid metabolism in the Brain – Fry, NPP
  • Growth Processes in Human Teeth – Dean , CDB
  • Drug metabolism and adverse drug reactions - Shephard, SMB
  • Age-related macular degeneration – Perkins, SMB
  • Nicotinic acetylcholine receptors in therapeutics and insecticides – Millar, NPP
  • A mouse model of attention deficit hyperactivity disorder (ADHD) – Stanford, NPP
  • Addiction and NK1 receptors – Hunt, CDB
  • Measurement & treatment of pain in infants – Fitzgerald, NPP
  • GABA receptors and mental health – Smart , NPP
  • Mechanism of action of gabapentinoid drugs – Dolphin, NPP
  • Nicotinic receptors and drug actions – Sivilotti, NPP
  • ATP and pathophysiology – King, NPP
  • Mechanisms of pain transmission and modulation – Dickenson, NPP
  • The biological basis of Battens disease – Mole, SMB
  • mTOR/S6K signaling in health and disease – Gout, SMB
  • The biology of aging – Gems, GEE
  • Hippocampal place cells and Alzheimers disease – O’Keefe, NPP
summary cont
Summary (cont)
  • Cell signalling pathways in age-related metabolic disease – Foukas, GEE
  • P2Y purinoceptors and colonic muscle – Townsend- Nicholson, SMB
  • Cone-jetting of concentrated biosuspensions- Townsend- Nicholson, SMB
  • Inherited susceptibility to complex disease – Dallas Swallow, GEE
mechanisms underlying the development of autonomic neuropathy in diabetes

Jill LincolnCell & Developmental Biology

  • The development of in vitro models of diabetes using adult
  • autonomic neurons exposed to stimuli that mimic the diabetic
  • environment for the investigation of mechanisms leading to
  • degeneration.
  • Using these models to assess potential therapeutic agents for
  • their ability to prevent or reverse diabetes-induced changes
  • prior to their application to in vivo animal models of diabetes.

Mechanisms underlying the development of autonomic neuropathy in diabetes.

slide5

Environmental regulators of osteoclasts (bone destroying cells) and osteoblasts (bone forming cells)

Tim Arnett

Cell & Developmental Biology

  • Our work has shown that:
  • Low ambient pH is the key activator of osteoclasts
  • Acid blocks bone mineralisation
  • Hypoxia is a major stimulator of osteoclast formation
  • Hypoxia blocks bone formation

These results help to explain the bone loss in many pathological settings, including kidney disease, inflammation, cancers, anaemias, diabetes and ageing – and will inform future treatments

  • We study the control of bone cell function by purinergic signalling via P2 receptors
  • Our key finding is that extracellular ATP is an important negative regulator of mineralisation

This work has implications for understanding the inappropriate mineralisation that occurs during ageing

Uttinget al (2006) Exp Cell Res 312: 1693-1702; Orrisset al (2007) Endocrinology 148: 4208-4216; Arnett (2008) J Nutr 138: 415-418S

adrian hobbs neuroscience physiology pharmacology

Pulmonary hypertension and myocardial infarction

Adrian Hobbs Neuroscience, Physiology & Pharmacology

Development of a novel combination therapy for pulmonary hypertension

  • Debilitating disease with a poor prognosis (5 year mortality ~45%)
  • Our innovation represents a new indication for two existing/licensed medicines
  • Convincing efficacy data in vitro and in vivo, including animals models of disease
  • Currently seeking funding for a Phase II trial
  • If successful, dual therapy should significantly advance treatment and considerably reduce healthcare costs
  • Collaboration with R. MacAllister (Clinical Pharmacology), C. Denton & G. Coghlan (RFH)

Design and development of small-molecule natriuretic peptide receptor (NPR)-C agonists for the prevention & treatment of myocardial infarction

  • Myocardial infarction major cause of death in the western world
  • We have identified & characterised key cytoprotective roles for C-type natriuretic peptide (CNP) in the cardiovascular system, triggered by NPR-C
  • Funded by a WT University Translational Award (UTA) for three years (2006-2009)
  • Synthesised 2 series of structurally-distinct NPR-C agonists (non-peptidic)
  • Filed composition of matter patents
  • Interest from 2 US-based Biotech companies, but looking for further funding to pursue development at UCL
  • Collaboration with S. Djordjevic (SMB), D. Selwood (WIBR), R. MacAllister (Clinical Pharmacology) & A. Ahluwalia (St. Bart’s)
chris taylorson structural and molecular biology

Antibody Directed Enzyme Drug Therapy

Chris TaylorsonStructural and Molecular Biology
  • Project gin collaboration with Kerry Chester at the UCL Cancer Institute, on Antibody Directed Enzyme Prodrug Therapy using mutated human enzymes.
  • Taylorson et al World Patent (1996) WO 96/20011
slide8

Nerve repair and demyelinating disease

KristjanJessen - Cell & Developmental Biology

  • We have found that:
  • c-Jun and Notch signalling
  • in Schwann cells is activated
  • in injured nerves and in
  • demyelinating neuropathies.
  • (ii) these signalling pathways drive
  • Schwann cell dedifferentiation.
  • This has direct implications for
  • nerve repair and demyelinating
  • disease

Schwann cells

dedifferentiate in

cut / injured nerves

Pathology

Acquired demyelinating

neuropathies

e.g. Guillain-Barre Syndrome

& Inherited demyelinating

neuropathies (CMT1A)

Pathological

Woodhoo A, et al. (2009)  Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nature Neurosci 12: 839-847.

slide9

From Advanced Biological FTIR Vibrational Spectroscopy to Medical Diagnostics

Peter Rich - Structural and Molecular Biology

Many different by IR spectroscopy, even in complex biological tissues and fluids. We are expanding our infrared spectroscopic expertise to applications in medical diagnostics, in collaboration with groups at Hammersmith and Royal Free Hospitals.

Example 2: 2D Imaging and Biochemical Mapping of Diseased Tissues

Example 1: Urine Analyses

Components currently quantitated from single IR spectra of human urine samples (in samples as small as 10 nanolitres:-

Diseased glomeruli (blue) in 0.6 x 0.6 mm kidney slice

Urea Glucose Lactose phosphate sulphate ammonium protein uratecreatinecreatininephospholipidoxalate acetoacetateß-hydroxybutyratepH (from ratio of the H2 PO4- /HPO42- forms of phosphate)

Normal

Diabetic

Full IR spectrum of each 5x5 micron pixel allows mapping and quantitation of numerous biochemicals and cell components

steroid metabolism in the brain
Steroid metabolism in the brain

Jonathan Fry

Neuroscience, Physiol. & Pharmacol

  • Several conditions e.g. stress, memory, ageing and central control of cardiovascular function are influenced by brain steroids.
  • Collaboration with John Honour's lab at UCLH identifying pathways of steroid metabolism in adult male rat brain. This work is now being carried forward in (an MRC-funded) collaboration with Thelma Lovick's lab in Birmingham to investigate how these steroids change during the ovarian cycle in the rat and to suggest interventions which might relieve dysphoria and pain (especially abdominal) during the cycle in women.
  • The Fry lab is one of the few labs capable of measuring (free and conjugated) steroids in plasma and urine and brain.
growth processes in human teeth
Growth processes in human teeth

Chris Dean

Cell and Developmental Biology

Below is a confocal image of fluorescing oxytetracycline label lines that chelate with calcium in mineralising dentine in a human tooth. Studying incremental markings in modern human and fossil primate teeth can reveal growth processes from the past and occasionally, combinations of growth process that do not exist today.

slide12

Drug metabolism and adverse drug reactions

Elizabeth Shephard

Structural and Molecular Biology

Mouse models to reveal role of FMOs in N- and S-oxidation

in multi-pathway drug metabolism

Hernandez,Drt al., (2009). Deletion of the mouse Fmo1 gene results in enhanced pharmacological

behavioural responses to imipramine. Pharmacogenetics and Genomics 19(4), 289-299.

2. Genetic polymorphisms:prediction of adverse drug reactions

and/or increased efficacy of drug treatment

Francois,A.A et al., (2009). Human flavin-containing monooxygenase 2.1 catalyzes oxygenation of the

antitubercular drugs thiacetazone and ethionamide. Drug Metabolism and Disposition 37, 178-186

3. Genetic polymorphisms: predicting individuals with alterations in the regulation of energy metabolism

neil millar neuroscience physiology pharmacology

Nicotinic acetylcholine receptors in

therapeutics and insecticides

Neil MillarNeuroscience Physiology & Pharmacology

Molecular pharmacological characterization of neuronal nicotinic acetylcholine receptors (nAChRs). Neuronal nAChRs are important targets for pharmaceutical drug discovery (for example, in the treatment of neurological and psychiatric disorders such as Alzheimer’s disease and schizophrenia). Neuronal nAChRs are also important targets for insecticides (neonicotinoids) that are used widely in crop protection and animal health applications.

Drug discovery research

The Millar lab has long-term collaborative links with and receives funding from the pharmaceutical company Eli Lilly (since 2001).

Insecticide discovery research

The Millar lab has long-term collaborative links with and receives funding from several healthcare and agroscience companies. These include Bayer CropScience (since 2006), Bayer HealthCare (since 2006), Dow AgroSciences (since 2003) Syngenta (formerly Zeneca Agrochemicals; since 1999).

a mouse model of attention deficit hyperactivity disorder adhd

Clare Stanford

Neuroscience, Physiology & Pharmacology

A mouse model of attention deficit hyperactivity disorder (ADHD)

Yan TC, Hunt SP, Stanford SC (2009) Behavioural and neurochemical abnormalities in mice lacking functional tachykinin-1 (NK1) receptors: A model of attention deficit hyperactivity disorder. Neuropharmacology. 2009 Sep 10. [Epub ahead of print] PMID: 19748515

stephen hunt cell developmental biology

Addiction research

Stephen Hunt Cell & Developmental Biology

We have found that a mouse that lacks one key receptor (NK1) is resistant to the pleasurable aspects of opiates and alcohol. NK1 gene polymorphisms have been found in samples taken from alcoholic humans and NK1 antagonists used to blunt withdrawal severity. We will use the mouse to drive our search for new therapies to prevent relapse into drug taking. ,, Hugh Gurling (Med)

Torsall A, et al., 2009 The neurokinin-1 receptor is required for alcohol reward and escalation of alcohol intake. Proc Natl Acad Sci U S A.

George DT, et al., 2008 Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism. Science.

Murtra, P, et al., 2000 Rewarding effects of opiates are absent in mice lacking the receptor for Substance P. Nature 405, 180-183

measurement treatment of pain in infants
Measurement & treatment of pain in infants

Maria Fitzgerald

Neuroscience, Physiology & Pharmacology

  • Electrophysiological analysis of nociceptive processing in the infant cortex
  • Differential analysis neuroimmune pathways activated by noxious event in infants and adults
  • Targetting genes whose expression is regulated in young versus adult pain models.

We are developing methods of measuring and treating

infant pain based on:

Fitzgerald M, Walker SM. Infant pain management: a developmental neurobiological approach. Nature Clin Pract Neurol. 2009 Jan;5(1):35-50. Review.

slide18

GABA receptors and mental health

Trevor Smart

Neuroscience, Physiology & Pharmacology

Inhibitory Synapse

Presynaptic

Areas of clinical interest

Epilepsy

Anxiety

Depression

Schizophrenia

Modulators/Drugs

GABA

ab

abg

abd

abg

Ischaemia/Stroke

Drug Abuse/Addiction

Synaptic

Receptors

Extrasynaptic

Receptors

Anaesthesia

Postsynaptic

Phosphorylation/Neurosteroids

Signalling/associated proteins

Receptor Trafficking

Drug Targeting

Receptor Dysfunction

Inhibitory Synaptic Plasticity

slide19

Mechanism of action of gabapentinoid drugs

Annette Dolphin

Neuroscience, Physiology & Pharmacology

She has identified that these drugs inhibit the trafficking of the calcium channel α2δ subunits, and their associated α 1 subunits, which form the channel pore.

Annette Dolphin’s group has been studying how the drugs gabapentin and pregabalin have their action.

These drugs are used in the treatment of neuropathic pain and in epilepsy. They bind to the α2δsubunits of calcium channels, but their mechanism of action was unknown.

HA-tagged

a1 subunit

a2d subunit

control

100 mM

Chronic GBP

This is a novel mechanism of action, and this work has resulted in the development of novel tools for use in calcium channel trafficking assays.

Hendrich et al (2008) PNAS (USA) 105: 3628–3633.

Walker and De Waard (TINS)

nicotinic receptors and drug actions
Nicotinic receptors and drug actions

Lucia Sivilotti

Neuroscience, Physiology & Pharmacology

We study how nicotinic superfamily receptors are activated at single-molecule level. These synaptic receptors mediate the effect of drugs such as benzodiazepines, nicotine and neuromuscular blockers and may be useful targets for novel treatments for pain and dementia.

We have brought new insight to the pharmacological question of what makes one drug is more effective than another on the same receptor.  We are now using our techniques to characterize the structure of the ACTIVATED receptor, ultimately to inform rational drug design.

Lape, Colquhoun & Sivilotti (2008) On the nature of partial agonism

in the nicotinic receptor superfamily, Nature,454, 722-7

atp and pathophysiology
ATP and pathophysiology

Brian King

Neuroscience, Physiology & Pharmacology

Two classes of receptors for extracellular ATP are found on the surface of epithelial cells. Their generic names are P2XR and P2YR. Epithelial cells, like all others, release packaged ATP when the cell wall is deformed - to locally activate P2XR and P2YR. This phenomenon happens in all hollow organs, where the secretion of salt and water across the cell wall can be finely regulated. This fundamental mechanism has implications for the physiology of the kidney, lungs and secretory ducts and in the pathophysiology of these organs (such as cystic fibrosis, asthma, diabetes insipidis). My current work focuses on the molecular mechanism for ATP export which is thought to involve pressure sensitive TRP-channels.

Wildman SSP, King BF (2008) P2X receptors: epithelial ion channels and regulators of salt and water transport.

Nephron Physiology, 108: 60-67.

Wildman SSP et a., (2009). Nucleotides downregulate aquaporin 2 via activation of apical P2 receptors.

JASN; 20: 1480-1490.

slide22

Mechanisms of pain transmission and modulation

Tony Dickenson

Neuroscience, Physiology & Pharmacology

  • Understanding plasticity in different pain states
  • The central mechanisms of pain transmission
  • The interplay between “bottom-up and top-down” processing
  • Mechanisms of action of licensed drugs
  • Probing roles of novel targets
  • Improvement in knowledge, identification of targets/mechanisms
  • Translation to the clinic- better understanding, better use of available therapies, patient explanations of their pains
  • Back translation from human imaging, unmet needs, signs and symptoms
  • Translation to drug discovery

D’MELLO RD, DICKENSON AH, Spinal cord mechanisms of pain Br J Anaesthesia 2008; 101: 8-16.

SUZUKI R, RYGH LJ, DICKENSON AH. Bad news from the brain: descending 5-HT pathways that

control spinal pain processing.Trends Pharmacol Sci. 2004; 25:613-7

slide23

The neuronal ceroid lipofuscinoses (Batten disease)

Sara Mole - Structural and Molecular Biology

A family of mainly children’s monogenetic neurodegenerative diseases, currently incurable act as proof of concept and provide targets of single genes which precipitate neurodegeneration and may contribute to more common and later ages of onset of neurodegeneration.

Basic science that is medically relevant: Understanding biological basis of NCL - identifying genes (8 so far), functional cell biology of these and model organism orthologues

Disease-driven research: Understanding disease - identifying pathways (using genetically tractable models; metabolomic changes; screening for drugs that alter disease phenotype) to provide better targets for therapy development

Patient-driven research: Improved diagnostics (up to date, streamlined, faster; stakeholder in National Batten Service NCG bid); Mutation database; NCL resource web site to provide information; Diagnostic algorithm, Book on Batten disease (2nd edition due 2010); Running of professional training courses; Scientific advisor to Batten disease Family Association; Consultant by tel and email enquiries

S Codlin and SE Mole. 2009. S. pombe btn1, the orthologue of the Batten disease gene CLN3, is required

for vacuole protein sorting of Cpy1p and Golgi exit of Vps10. J Cell Sci. 122: 1163-1173.

slide24

mTOR/S6K signaling in health and disease

NUTRIENTS

CYTOKINES

MITOGENS

Ivan Gout

Structural and Molecular Biology

AMP ; ATP

METABOLITES

mTOR

S6K

Cell survival

Autophagy

Glucose

homeostasis

Cell Growth & Proliferation

N

D

Y

O

Angiogenesis

S

I

R

T

E

A

G

L

U

Cancer

Diabetes

Inflamation

Neurodegeneration

  • We hold 3 patents on the mTOR/S6K signaling
  • S6K has been selected by UCL as a target for MRC Translational program
  • In collaboration with the Ludwig Institute for Cancer Research we run a Clinical Drug Discovery Program on S6 kinase
slide25

The Biology of Ageing

100

% Survival

50

0

0

0

12

24

36

15

30

45

60

25

50

75

100

Time (days)

Time (days)

Time (months)

Genotype Median lifespan

+ 16 days

daf-2 35 days

Genotype Median lifespan

+/+ 44 days

chico/+ 60 days

chico/chico 65 days

Genotype Median lifespan

+/+ 18.7 months

Igf1r+/- 24.9 months

David Gems

Genetics, Evolution and Environment

Insulin/IGF-1 signaling controls ageing:

Irs1 mutant mice have delayed ageing. Selman, Gems, Partridge, Withers, FASEB J. 2008

hippocampal place cells and alzheimers disease
Hippocampal place cells and Alzheimers disease

John O’Keefe

Neuroscience, Physiology & Pharmacology

Alzheimer's disease (AD) is associated with progressive memory decline. It is now widely accepted that β-amyloid (Aβ) plays a central role in the pathogenesis of AD and part of this disorder may consist of an Aβ-induced synaptic failure. Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. We have recorded place cells in the Tg2576 mouse model of AD, which expresses a human amyloid precursor protein (APP) variant linked to AD, leading to an age-dependent deposition of amyloid plaques. We report that aged (16 months) but not young (3 months) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals’ (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Place cell recording provides a new sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies.

Cacucci F, Yi M, Wills TJ, Chapman P, O'Keefe J. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7863-8.

slide27

Cell signalling pathways age-related

metabolic disease

Lazaros Foukas, Genetics, Evolution, Environment

Cell signalling pathways are increasingly targeted in the therapy of diseases such as

cancer, diabetes and inflammation

  • Insulin/IGF-1 signalling pathway : Mutations extend healthspan of model organisms
  • PI-3 kinase (PI3K): Key node in the insulin /IGF-1 pathway. Mutated in approx. 30% of various cancers
  • Currently being pursued as therapeutic target in oncology
  • Type 2 diabetes and metabolic syndrome: Age is the single most important risk factor

Aim: Use animal models to provide proof-of-principle that the PI3K signalling pathway can be therapeutically targeted in middle-aged and old individuals to prevent/ ameliorate type-2 diabetes and metabolic syndrome.

Graupera, M., et al. (2008) Nature 453, 662-668. Foukas, L. C., et al. (2006) Nature 441, 366-370.

slide28

P2Y purinoceptors and colonic muscle

Andrea Townsend-Nicholson, Structural & Molecular Biology

slide29

Cone-jetting of concentrated biosuspensions

Andrea Townsend-Nicholson - Structural & Molecular Biology

slide30

Inherited susceptibility to complex disease

Dallas Swallow

Genetics, Environment & Evolution

Inherited variations in gene expression & gene function, and significance to phenotype

APPROACHES:

TOPICS:

  • mucins
  • lactase
  • Gilbert’s syndrome -UGT1A1
  • Other drug metabolising enzymes
  • Expression studies
  • Genotype/phenotype association studies
  • Epidemiology
  • Population studies

OUTCOMES:

Understanding: mechanism; susceptibility to complex disease; differences according to ancestry

THEMES:

GI/Hep

Respiratory