P2 presentation.pptx

8/18/2019 P2 presentation.pptx

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Regulating Liver Fibrosis with Tyrosine Kinase Inhibitors

Natalia Veronica (A00988!"#

$e%art&ent o' har&acy) Faculty *cience

Final +ear ro,ect %resentation

*u%ervisor- Associate ro'essor .o .an Kiat


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What is liver fibrosis

Liver fibrosis:

/1cessive accu&ulation o' e1tracellular &atri1 in res%onse to chronic

liver in,ury

2irrhotic

liver

Nor&al

liver

Fibrotic

liver

2ancerous liver

(he%atocellular

carcino&a#

2hronic in,ury-

/ Viral in'ection(.e%atitis 3 an4 2#/ Alcohol

Roc5ey $2) Frie4&an *L6 .e%atic Fibrosis an4 2irrhosis6 07-:8;6

7 o' 8


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Complications of liver fibrosis

76 "e&al A) 3ray F) 2enter L?3?2AN 076

International journal of cancer. Mar 1 2015;16(5):!59-"6.

o' 8

Increases ris5 o'

he%atocellular carcino&a

(.22#

.22 accounts 'or 70 % to 85 % o' the totalliver cancer bur4en worl4wi4e

In men) liver cancer is the 5th

lea4ing cause o' cancer 4eath6

In women) liver cancer is the 9th

lea4ing cause o' cancer 4eath6

Liver cirrhosis


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Reglation of e!tracelllar matri!

"#C$ homeostasis


@ o' 8

Fibrotic

liver

$atri!

homeostasis


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Crrent therapetic options


; o' 8

2hronic liver in,ury

Ku%''er cellsT cellsNK cells

Recruit&ent o'

in'la&&atory cells

Release o' cyto5ines

Cuiescent .*2s Activate4 .*2s

Activation

❶In,ury

❷In'la&&ation

❸ Activation o' .*2san4 'ibrogenesis

/ Alcohol

abstinence/ Antiviral thera%y

(anti:he%atitis 3

an4 2#

∗Ris5 o' reversion

to 'ibrosis

2orticosteroi4s

DInco&%lete

su%%ression

'ibrogenesis

Target 'ibrogenicsignaling in .*2s

Liver trans%lantation is the only curative treat&ent 'or en4 stage liver 'ibrosis

DLi&ite4 organ 4onor an4 co&%atibility


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'ibrogenic signaling in +,Cs

-erochemical/2annabinoi4s/?%ioi4s/*erotonin

Dcannabinoi4

inhibitions lea4s to4e%ression

Renin.angiotensin

s*stem

Dless

%rogression in

in'la&&ationbut not in

'ibrosis

#n/othelin an/

nitric o!i/e

1/ipo2ines

)*rosine

2inases

-clearreceptors:/ARE/FR/R

1ctivate/ +,Cs

2ohen:Na'taly


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)*rosine 2inases involve/ in liver

fibrosis

/ Activate4 .*2s have increasee1%ression o' tyrosine 5inase

rece%tors-/Vascular en4otheliu& growth

'actor rece%tors (V>FR#

/Fibroblast growth 'actorrece%tors (F>FR#

/latelet 4erive4 growth 'actor

rece%tors ($>FR#

Cu K) .uang G) Lin T) et al6 New Insight into the Anti:liver Fibrosis ''ect o'


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(reliminar* st/ies

/?%ti&al increase/

e1%ression o' :*


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+*pothesis9 o' 8

Tyrosine

5inase

inhibitors

Increase


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bectives70 o' 8

❶To o%ti&ise in-&itro liver 'ibrotic &o4el using L: cells sti&ulate4with T>F:J7

❷ To 4eter&ine using this o%ti&ise4 &o4el) tyrosine 5inase inhibitorse''icacy in reversing liver 'ibrosis s%eci'ically by re/cing )I$(s

e!pression an/ increasing $$(s e!pression

u) L6) .ui) A6 +6) Albanis) 6) Arthur)


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$etho/olog*.in vitro fibrotic mo/el

optimisation 77 o' 8


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$etho/olog*.t*rosine 2inase

inhibitors efficac* 7 o' 8


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$etho/olog*.gene an/ protein

anal*sis

$$(4; $$(


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)*rosine 2inase inhibitors7 o' 8

AG$;!

3>"@98

$7!@0!

3I3F770

*ora'enib


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Concentration /epen/ent effects of

)'.6ene e!pression following /ifferent concentrations of )'.6

7; o' 8

Increase/ TI


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)ime /epen/ent effects of )'.6

ene e!pression following 4 ngmL )'.6

7 o' 8

.ighest TI


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ptimise/ con/itions

#!tensive fibrogenesis "matri! s*nthesis an/ minimal

fibrinol*sis "matri! /egra/ation

$atri!

homeostasis

Increased

fbrogenesis

Reduced

fbrinolysis

Matrixaccumulation

1t 4 ngmL )'. 6 for 4 hor:

M :*


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)*rosine 2inase inhibitors

/ecrease/ )I$( gene e!pression

,orafenib

1>&57 ?@


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)*rosine 2inase inhibitors

/ecrease/ )I$(4 gene e!pression

,orafenib

1>&57 ?@


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)*rosine 2inase inhibitors /ecrease/ )I$(

an/ )I$(4 protein e!pression0 o' 8

&ecrease/ TI


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an/ )I$(4 protein e!pression7 o' 8

?I?'40

&ecrease/ TI


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an/ )I$(4 protein e!pression

,orafenib

o' 8

&ecrease/ TI


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)*rosine 2inase inhibitors increase/ $$(4

gene e!pression

,orafenib

1>&57 ?I?'40 ?@


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)*rosine 2inase inhibitors increase/ $$(<

gene e!pression

,orafenib

1>&57 ?I?'40 ?@


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)*rosine 2inase inhibitors treatment o' 8

/ ?@&57 showe4 &ore %ro&inent increase in

$$(s

Tyrosine

5inaseinhibitors


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'tre st/ies

❷

$eter&ine changes in

%rotein e1%ression o'


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Conclsion

/ Tyrosine 5inase inhibitors-/ Alter the balance between e1tracellular &atri1 4egra4ation an4 synthesis/ Increase F:β1 activated LX-2cells


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1c2nowle/gement

Associate ro'essor .o .an Kiat

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