Bedeutung der W4R MLP-Mutation für die kardiale Mechanotransduktion und die Entwicklung einer Kardiomyopathie
Zusammenfassung der Projektergebnisse
Cardiovascular diseases (CVDs), including heart failure, are the single most prevalent cause of death globally. Although major advances have been achieved during the last decades, our understanding of the underlying molecular mechanisms, the precondition for the development of novel therapeutic strategies, remains incomplete. In this context, mechanosensation, the process by which a cell senses various mechanical stimuli and ultimately converts them into biomechanical pathways, is a fundamental process present in every living cell. In cardiac myocytes the perception of changes in cellular geometry is linked to the Z-disk, a structure which defines the lateral borders of sarcomeres, the smallest functional units of striated muscles. Mechanosensation also is linked to a recently described novel type of cell death termed "mechanoptosis", a form of programmed cell death (apoptosis) only found after an increase in biomechanical stress in striated muscles. The Z-disk also is linked via "Z-disk mechano - transcriptional coupling (ZMTC)" to gene regulation. Moreover, the discovery of mutations in a wide variety of Z-disc proteins, which lead to perturbations in mechanosensation and mechanoptosis, gives rise to a diverse group of diseases which can be termed "Z-discopathies". The development of anti-mechanoptotic agents offers novel therapeutic strategies to combat Z-discopathies, including heart failure, otherwise lethal conditions.
Projektbezogene Publikationen (Auswahl)
- Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression. Circulation. 2006;113(23):2724-2732
Kögler H, Schott P, Toischer K, Milting H, Van PN, Kohlhaas M, Grebe C, Kassner A, Domeier E, Teucher N, Seidler T, Knöll R, Maier LS, El-Banayosy A, Korfer R, Hasenfuss G
- Reversal of calcium cycling defects in advanced heart failure toward molecular therapy. J Am Coll Cardiol. 2006;48(9 Suppl 1):A15-23
Hoshijima M, Knöll R, Pashmforoush M, Chien KR
- Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation. 2007;116(5):515-525
Knöll R, Postel R, Wang J, Kratzner R, Hennecke G, Vacaru AM, Vakeel P, Schubert C, Murthy K, Rana BK, Kube D, Knoll G, Schafer K, Hayashi T, Holm T, Kimura A, Schork N, Toliat MR, Nurnberg P, Schultheiss HP, Schaper W, Schaper J, Bos E, Den Hertog J, van Eeden FJ, Peters PJ, Hasenfuss G, Chien KR, Bakkers J
- Disease-modifying mutations in familial hypertrophic cardiomyopathy: complexity from simplicity. Circulation. 2008;117(14):1775-1777
Hilfiker-Kleiner D, Knöll R
- Elevated Afterload, Neuroendocrine Stimulation, and Human Heart Failure Increase BNP Levels and Inhibit Preload-Dependent SERCA Upregulation. Circulation Heart Failure. 2008;1:265-27
Toischer K, Kögler H, Tenderich G, Grebe C, Seidler T, N. N, Jung K, Knöll R, Körfer R, Hasenfuss G
- Human mutation in the anti-apoptotic heat shock protein 20 abrogates its cardioprotective effects. The Journal of biological chemistry. 2008;283(48):33465- 33471
Nicolaou P, Knöll R, Haghighi K, Fan GC, Dorn GW, 2nd, Hasenfub G, Kranias EG
- Zebrafish integrin-linked kinase is required in skeletal muscles for strengthening the integrin-ECM adhesion complex. Dev Biol. 2008;318(1):92-101
Postel R, Vakeel P, Topczewski J, Knöll R, Bakkers J
- Melusin gene (ITGB1BP2) nucleotide variations study in hypertensive and cardiopathic patients. BMC Med Genet. 2009;10:140
Palumbo V, Segat L, Padovan L, Amoroso A, Trimarco B, Izzo R, Lembo G, Zagrosek VR, Knöll R, Brancaccio M, Tarone G, Crovella S
- MLP: a stress sensor goes nuclear. J Mol Cell Cardiol. 2009;47(4):423-425
Gunkel S, Heineke J, Hilfiker-Kleiner D, Knöll R
- Muscle Research and Gene Ontology: New standards for improved data integration. BMC medical genomics. 2009;2(1):6
Feltrin E, Campanaro S, Diehl AD, Ehler E, Faulkner G, Fordham J, Gardin C, Harris M, Hill D, Knöll R, Laveder P, Mittempergher L, Nori A, Reggiani C, Sorrentino V, Volpe P, Zara I, Valle G, Deegan JNC
- A common MLP (muscle LIM protein) variant is associated with cardiomyopathy. Circ Res. 2010 106(4):695-704
Knöll R, Kostin S, Klede S, Savvatis K, Klinge L, Stehle I, Gunkel S, Kotter S, Babicz K, Sohns M, Miocic S, Didie M, Knöll G, Zimmermann WH, Thelen P, Bickeboller H, Maier LS, Schaper W, Schaper J, Kraft T, Tschöpe C, Linke WA, Chien KR
- Cardiac Mechanosensation & Clinical Implications. European Journal of Cardiovascular Medicine. 2010;1(II):33-37
Knöll R, Linke W
- elethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart. Circ Res. 2011;109(7):758-769
Knöll R, Linke WA, Zou P, Miocic S, Kostin S, Buyandelger B, Ku CH, Neef S, Bug M, Schafer K, Knoll G, Felkin LE, Wessels J, Toischer K, Hagn F, Kessler H, Didie M, Quentin T, Maier LS, Teucher N, Unsold B, Schmidt A, Birks EJ, Gunkel S, Lang P, Granzier H, Zimmermann WH, Field LJ, Faulkner G, Dobbelstein M, Barton PJ, Sattler M, Wilmanns M, Chien KR
- Genetics of mechanosensation in the heart. J Cardiovasc Transl Res. 2011;4(3):238-244
Buyandelger B, Ng KE, Miocic S, Gunkel S, Piotrowska I, Ku CH, Knöll R
- MLP (muscle LIM protein) as a stress sensor in the heart. Pflugers Arch. 2011;462(1):135-142
Buyandelger B, Ng KE, Miocic S, Piotrowska I, Gunkel S, Ku CH, Knöll R
- The sarcomeric Z-disc and Z-discopathies. J Biomed Biotechnol. 2011;2011:569628
Knöll R, Buyandelger B, Lab M
- Towards a re-definition of 'cardiac hypertrophy' through a rational characterization of left ventricular phenotypes: a position paper of the Working Group 'Myocardial Function' of the ESC. Eur J Heart Fail. 2011;13(8):811-819
Knöll R, Iaccarino G, Tarone G, Hilfiker-Kleiner D, Bauersachs J, Leite-Moreira AF, Sugden PH, Balligand JL
