Lars Maegdefessel

Ragnar Söderbergforskare i medicin // År: 2014 //
Anslagsförvaltare: Karolinska Institutet // Belopp: 8 000 000 kr

Min forskning

Icke-kodande RNA vid hjärt- och kärlsjukdomar

Lars Maegdefessels forskning syftar till att ta fram nya strategier för att upptäcka och behandla hjärt- och kärlsjukdomar. Han använder ny kunskap om icke-kodande RNA för att förstå uppkomst av dessa sjukdomar, framför allt förträngning av halspulsådern och bråck på stora kroppspulsådern. 

Vårt arbete syftar till att ta fram nya diagnostiska och terapeutiska strategier för att begränsa utveckling och konsekvens av dessa sjukdomar i allmänhet, samt förträngning av halspulsådern (främsta orsaken till stroke) och bråck på stora kroppspulsådern i synnerhet.

Nyligen har icke-kodande RNA med så kallad antisens-kapacitet fått mycket uppmärksamhet då de har visat sig kunna nedreglera geners uttryck på transkriptionell och post-transkriptionell nivå. Den hittills mest studerade icke-kodande underarten av RNA är mikroRNA. Denna tros finjustera translationell produktion av messengerRNA (mRNA) genom att antingen främja nedbrytning av mRNA eller hämma omvandling till protein.

Forskningsprojektet fokuserar på manipulering av uttrycket av icke-kodande RNA och betydelsen av detta för utveckling. Fokus ligger även på behandling av hjärt- och kärlsjukdomar för att kritiskt granska framtida terapeutiska strategier med avseende på klinisk och translationell genomförbarhet.

Research

Cardiovascular disease (CVD) remains the most prevalent reason for human morbidity and mortality in the Western hemisphere. The discovery of an entirely new method of gene regulation by non-coding RNAs (e.g., microRNAs, long-non-coding-RNAs, Natural Antisense Transcripts) and their validation as key modulators of CVD provides new hope for innovative therapeutical approaches and disease recognition.

With the discovery of non-coding RNAs being powerful regulators in a wide variety of diseases, it is only a logical consequence that the possibilities of viewing them as therapeutic and diagnostic entities are being explored. The most important difference between modulating non-coding RNAs (like microRNAs) and the traditional approach of therapy is that traditional drugs have specific cellular targets, whereas non-coding RNAs can modulate an entire functional network. My research group is particularly interested in discovering non-coding RNAs being responsible for atherosclerotic plaque vulnerability in carotid stenosis as well as abdominal aortic aneurysm development and acute rupture.

With this currently submitted proposal we describe our approach of profiling unique human tissue biobank material and functional experimental in vivo models, enabling us to discover novel and beneficial therapeutic strategies on the molecular level to combat the burden of the investigated diseases.

Publikationer i urval

Karunakaran D, Thrush AB, Nguyen MA, Richards L, Geoffrion M, Singaravelu R, Ramphos E, Shangari P, Ouimet M, Pezacki JP, Moore KJ, Perisic L, Maegdefessel L, Hedin U, Harper ME, Rayner KJ. Macrophage mitochondrial energy status regulates cholesterol efflux and is enhanced by anti-miR33 in atherosclerosis. Circ Res. 2015; May 22nd. [Epub ahead of print]

Nurnberg, ST, Cheng K, Raiesdana A, Kundu R, Miller CL, Arora K, Carcamo-Oribe I, Xiong Y, Kim YB, Tellakula N, Murthy N, Boisvert WA, Hedin U, Perisisic L, Maegdefessel L, Pjanic M, Owens GK, Tallquist MD, Quertermous T. Coronary artery disease associated transcription factor TCF21 regulates smooth muscle precursor cells that contribute to the fibrous cap. PLoS Genetics. 2015; May 28;11(5):e1005155.

Maegdefessel L, Rayner KJ, Leeper NJ. MicroRNA Regulation of vascular smooth muscle function and phenotype. Arterioscler Thromb Vasc Biol. 2015; 35:2-6.

Raaz U, Zoellner A, Schellinger I, Toh R, Nakagami F, Brandt M, Emrich F, Kayama Y, Eken SM, Adam M, Maegdefessel L, Hertel T, Deng A, Jagger A, Buerke M, Dalman RL, Spin JM, Kuhl E, Tsao PS. Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development. Circulation. 2015; 131:1783-95.

Maegdefessel L, Spin JM, Raaz U, Adam M, Azuma J, Toh RM, Deng A, Chernogubova E, Eken SM, Jin H, Roy J, Hultgren R, Caidahl K, Schrepfer S, Mc Connell MV, Hamsten A, Eriksson P, Dalman RL, Tsao PS. miR-24 limits aortic vascular inflammation and murine abdominal aortic aneurysm development. Nat Commun. 2014; 5:5214.

Maegdefessel L, Dalman RL, Tsao PS. Pathogenesis of abdominal aortic aneurysms: microRNAs, proteases, genetic associations. Annu Rev Med. 2014; 65: 49-62.

Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L, Bolanos JP, Rakovic A, Spin JM, Stubbendorff M, Ikeno F, Langer F, Zeller T, Schulte-Uentrop L, Stöhr A, Itagaki R, Haddad F, Eschenhagen T, Blankenberg S, Kiefmann R, Reichenspurner H, Velden J, Klein C, Yeung A, Robbins RC, Tsao PS, Schrepfer S. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature. 2014; 509:641-44.

Maegdefessel L. The emerging role of microRNAs in cardiovascular disease. J Intern Med. 2014; 276:633-44.

Miller CL, Haas U, Diaz R, Leeper NJ, Kundu RK, Patolla B, Assimes TL, Kaiser FJ, Perisic L, Hedin U, Maegdefessel L, Schunkert H, Erdmann J, Quertermous T, Sczakiel G. Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation. PLoS Genetics. 2014; 10:e1004263.

Kojima Y, Downing K, Kundu R, Miller C, Dewey F, Lancero H, Raaz U, Perisic L, Hedin U, Schadt E, Maegdefessel L, Quertermous T, Leeper NJ. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. J Clin Invest. 2014; 124:1083-97.

Eken SM, Jin H, Chernogubova E, Maegdefessel L. Making sense in antisense: therapeutic potential of noncoding RNAs in diabetes-induced vascular dysfunction. J Diabetes Res. 2013; 2013:834727.

Maegdefessel L. Therapeutic potential of modulating microRNAs in vascular disease. Curr Vasc Pharmacol. 2013 May 13 [Epub ahead of print] (IF: 2.9)

Maegdefessel L, Azuma J, Toh RM, Merk DR, Deng A, Raiesdana A, Leeper NJ, Raaz, U, Schoelmerich A, Mc Connell MV, Dalman RL, Spin JM, Tsao PS. Induction of microRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med. 2012; 4:122ra22.

Maegdefessel L, Azuma J, Toh RM, Merk DR, Deng A, Chin JT, Raiesdana A, Leeper NJ, Raaz, U, Schoelmerich A, Mc Connell MV, Dalman RL, Spin JM, Tsao PS. Inhibition of microRNA-29b reduces abdominal aortic aneurysm development. J Clin Invest. 2012; 122:497-506.

Merk DR, Chin JT, Dake BA, Maegdefessel L, Miller M, Kimura N, Tsao PS, Spin JM, Mohr FW, Robbins RC, Fischbein MP. miR-29b Participates in Early Aneurysm Development in Marfan Syndrome. Circ Res. 2011; 110:312-24.