Využitie mikro-rna v objasnení vzťahu medzi srdcovým zlyhávaním a osteoporózou. MUDr. Martin Kužma, PhD. V. Interná klinika LF UK a UN Bratislava, SR

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1 Využitie mikro-rna v objasnení vzťahu medzi srdcovým zlyhávaním a osteoporózou MUDr. Martin Kužma, PhD. V. Interná klinika LF UK a UN Bratislava, SR

2 Mikro-RNA Malé nekodujúce úseky RNA dĺžky nukleotidov Prvý krát popísané v r 1993 u parazita Caenorhabditis elegans Lee RC. Et al. Cell 1993

3 Publikácie s mirna Viac ako 38 tis. typov mirna (zdroj: mirbase.org; ofic. databáza mirna) do pubmed.nih.gov: článkov zaoberajúcich sa mirna

4 Prečo je mikro-rna tak dôležité?

5 Využitie mirna mirna otvorila nové možnosti štúdia expresie génov Je známe že mirna je zapojená do génovej regulácie normálneho vývoja ako aj patogenézy chorôb

6 Vzťah osteoporóza-srdcové zlyhávanie Obidve ochorenia sú prevalentné, hlavne v starobe Fraktúry krčka femuru sú 2-3 x častejšie u pacientov s CHSZ Pacienti s CHSZ >65 r. 4x vyššie riziko akejkoľvek fraktúry Sennerby U, Osteoporos Int 2007 Carbone L et al EHJ 2010

7 Vzťah osteoporóza-srdcové zlyhávanie?? fraktúry dôsledok CHSZ alebo rizikových faktorov?? RF : 25 OH D3 Telesný výkon - sarkopénia?? vek Obličková choroba Diabetes Postmenopauza u žien Carbone L et al EHJ 2010

8 Vzťah osteoporóza-srdcové zlyhávanie osteoporóza CHSZ Fraktúry Rizikové faktory sarkopénia

9 Osteoporóza Nerovnováha medzi kostnou formáciou (osteoblasty) a kostnou resorpciou (osteoklasty) Regulovaná cytokínmi, hormónmi a rastovými faktormi Do procesu differenciácie a ovplyvňovania funckie kostných buniek sú zahrnuté aj mirna Tang P. et al. RNA Biology 2014

10 Zapojenie mirna do procesu kostnej prestavby Tang P. et al. RNA Biology 2014

11 Srdcové zlyhávanie SZ je komplexný syndróm definovaný neadekvátnym srdcový výdajom k tomu aby zabezpečil metabolické potreby tkanív Hlavná príčina hospitalizácie dospelých nad 65 rokov

12 Rizikové faktory SZ

13 Neurohormonálna regulácia srdca Neurohormóny Neprospešné - Inadekvátne mechanizmy Prospešné - Kompenzačné Wong Lee, Int J Mol Sci 2016

14 Bimarkery SZ mirna??

15 mirna a SZ Konsenzus ohladne mi RNA a SZ existuje u viac ako 20 štúdii Problémom bývajú prídavné faktory: fenotyp ochorenia, akútnosť, závažnosť, stupeň kompenzácie (kontroly) ochorenia Doteraz bolo identifikovaných viac ako 70 rôznych mirna uplatňujúcich sa v regulácii CHSZ

16 mirna v predikcii SZ 225 subjektov, 75 bez SZ, 75 so SZ (s poklesom EF), 75 so SZ (bez poklesu EF) 5 typov mirna v predikcii SZ Wattson et al EJHF 2015

17 NTproBNP Marker využívaný v klin praxi Nedostatočná senzitivita Využívný k podpore dg SZ

18 mirna + NTproBNP vyššia senzitivita diagnózy CHSZ Wattson et al EJHF 2015

19 Analýz 30 kontrol, 30 pac. s SZ (s redukovanou EF) a 30 so SZ (bez redukovanej EF ) Potvrdilo 12 mirna (z 344) s diagnostickým potenciálom pre jedna alebo oba fenotypy SZ. Wong L, EJHF 2015

20 MiRNA ako možný biomarker fraktúr 20 pac. s fraktúrou krčka vs. 20 zdravých Seeliger C., et al. JBMR 2014

21 Rôzne úrovne regulácie kostných buniek Tang P. et al. RNA Biology 2014

22 mirna podľa typu osteoporózy 36 pacientov s OP fraktúrami vs. 39 kontrol ; analýza 187 typov mirna, mir-550a-5p, mir-550a-3p, mir-188-3p, mir-382-3p, mir-155-5p, mir-942-5p, mir-330-3p, mir-203a, mir-181c-5p 9 typov bolo signif. regulovaných u všetkých troch skupín R.Kocijan et al. J Clin Endocrinol, Metab, November 2016, 101(11):

23 mirna podľa typu osteoporózy 19 of 91 regulated mirnas (21%) were found differently regulated in all patients with low-traumatic fractures when compared with subjects without fractures. R.Kocijan et al. J Clin Endocrinol, Metab, November 2016, 101(11):

24 Špecifické klustre mi-rna (nájdené u pac. s SZ) redukujú aj iné procesy na úrovni buniek mirna: 125a-5p, -193b-3p, p

25 Zapojenie mirna do procesu kostnej prestavby Tang P. et al. RNA Biology 2014

26 Zapojenie mirna do procesu kostnej prestavby Lian et al. Nat Rev Endocrinol 2013

27 mirna ako link medzi OP a CHSZ? Existuje niekĺko typov mirna,ktoré sa up- /down- regulované zároveń u pacientov so SZ a osteoporotickými fraktúrami Neexistujú štúdie ktoré by skúmali asociáciu týchto mirna špecificky k rôznym typom SZ vo vzťahu k vzniku osteoporotických fraktúr, liečbe SZ

28 Budúcnosť? Využitie mirna ako biomarkera fraktúr, závažnosti osteoporózy, odpovede na liečbu by mohlo viesť k individualizácii liečby SZ a osteoporózy podľa mirna Lepšiu kvalitu života pacientov so SZ (bez OP.fraktúry, po nej)

29 Ďakujem za pozornosť

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