ErythropoietinErythropoietin Known as EPOKnown as EPO MW 30400DaMW 30400Da Discovered by Miyake et al Discovered by Miyake et al

1977from urine of anaemic 1977from urine of anaemic pts.pts.

LC 4 alpha helical bundle LC 4 alpha helical bundle class 1 cytokineclass 1 cytokine

193 a.a. human (192 mouse)193 a.a. human (192 mouse) When levels low e.g.in CRF, When levels low e.g.in CRF,

chemotherapy treatment in chemotherapy treatment in cancercancer

not effective when levels are not effective when levels are high (high altitude, hypoxia due high (high altitude, hypoxia due to CHD)to CHD)

Has been used in AIDSHas been used in AIDS

Biological FunctionsBiological Functions

As its name suggests, EPO As its name suggests, EPO stimulates growth of Erythrocytesstimulates growth of Erythrocytes

It increases as a result of a negative It increases as a result of a negative feedback loop-low feedback loop-low Oxygen=production of Epo. Oxygen=production of Epo.

Produced in the Kidneys and also in Produced in the Kidneys and also in the Liver ( as Foetus: liver only)the Liver ( as Foetus: liver only)

Carries oxygen in bloodCarries oxygen in blood

Therapeutic UsesTherapeutic Uses

When Epo levels low-used in When Epo levels low-used in aneamia resulting from aneamia resulting from chemotherapy, AIDS, CRFchemotherapy, AIDS, CRF

Not useful if levels already high as Not useful if levels already high as in cases of hypoxia, high altitude in cases of hypoxia, high altitude living, CHD and lung disease.living, CHD and lung disease.

Shown to improve QOL greatly in Shown to improve QOL greatly in vast majority of cancer/AIDS ptsvast majority of cancer/AIDS pts

RHu Epo in treatment of RHu Epo in treatment of Anaemia of CancerAnaemia of Cancer

Low levels of Epo Low levels of Epo resulting from the resulting from the treatment of treatment of CancerCancer

treated by RHuEpotreated by RHuEpo improves Quality improves Quality

of lifeof life improves anaemia improves anaemia

in hypo-Epo casesin hypo-Epo cases

Peptide MimeticsPeptide Mimetics Enables the use of Enables the use of

Epo in therapy for Epo in therapy for CRF and cancer CRF and cancer without unwanted without unwanted immunological immunological effectseffects

synthesised from synthesised from random peptide random peptide ‘libraries’ displayed ‘libraries’ displayed on filamentous on filamentous phages ( Bacterial phages ( Bacterial virus)virus)

These bind to and These bind to and activate a receptor of activate a receptor of cytokines similarly to cytokines similarly to original cytokine.original cytokine.

14-20 a.a. In length, 14-20 a.a. In length, serve as lead serve as lead compounds for compounds for development of development of therapeutically therapeutically effective Epo,smaller, effective Epo,smaller, less side effectsless side effects

Epo also has Epo also has therapeutic therapeutic AbAbusesuses

Used in sports to Used in sports to improve improve enduranceendurance

now detected now detected from naturally from naturally occurring EPO by occurring EPO by protein markers protein markers appearing post-appearing post-injection injection

Erythropoietin ReceptorErythropoietin Receptor

Hetero-dimer Hetero-dimer consisting of Beta consisting of Beta sheetssheets

Optimum Optimum effectiveness if effectiveness if 120 deg. to epo120 deg. to epo

works on JAK-stat works on JAK-stat pathwaypathway

stimulates NF-k Bstimulates NF-k B protects against protects against

agoptosisagoptosis

Optimum Effect with Optimum Effect with 120 degree receptor 120 degree receptor

angleangle

‘‘Epo imposes a Epo imposes a unique 120 unique 120 degree angular degree angular orientation that orientation that is responsible for is responsible for optimum optimum signalling signalling potential through potential through intracellular intracellular kinase pathways’kinase pathways’

Stimulation of Nuclear Stimulation of Nuclear Factor kappa B by EpoFactor kappa B by Epo

Not JAK2 Not JAK2 dependentdependent

NFkB described as NFkB described as control switch for control switch for gene transmission gene transmission (on/off).(on/off).

Protects against Protects against apoptosisapoptosis

new evidence for new evidence for neuroprotectionneuroprotection

New EvidenceNew Evidence for for EpoEpo inin PNS PNS

Thought to protect neural network Thought to protect neural network by NF kappa B stimulationby NF kappa B stimulation

Evidence that Evidence that neuroprotectiveneuroprotective nature of Epo useful post-CVAnature of Epo useful post-CVA

More evidence for More evidence for neuroimmunomodulation (adds to neuroimmunomodulation (adds to Psychoneuroimmunological data)Psychoneuroimmunological data)

Epo is Epo is protectiveprotective--in neural networksin neural networks

and and during erthrocyte during erthrocyte developmentdevelopment

May be used in treatment May be used in treatment of of strokestroke victims victims

Protects against RBC Protects against RBC apoptosis apoptosis with NFkB with NFkB

stimulationstimulation

Erythropoietin:Erythropoietin:

Oxygen transport-Oxygen transport-protection-protection-

Therapeutic uses-Therapeutic uses-

and abuses !and abuses !