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dc.contributor.advisorSolaro, Ross J.en_US
dc.contributor.authorYar, Sumeyyeen_US
dc.date.accessioned2014-02-24T18:40:28Z
dc.date.available2014-02-24T18:40:28Z
dc.date.created2013-12en_US
dc.date.issued2014-02-24
dc.date.submitted2013-12en_US
dc.identifier.urihttp://hdl.handle.net/10027/11257
dc.description.abstractThe work presented in this thesis addresses major gaps in our understanding of how thin filament control mechanisms translate to regulate cardiac function. Here we focus on α-tropomyosin (α-TM) as a nodal point in control of the thin filament state. α-TM carries a conserved, charged residue (Asp137) located in the hydrophobic core of its coiled-coil structure.This is distinct to the α-TM coiled-coil in that the residue is found at a position typically occupied by a hydrophobic residue.Via substituting this Asp137 with a more expected canonical Leu, it was previously shown that Asp137 destabilizes a region in the middle of α-TM, inducing a more flexible local region that is important for modulating the cooperative activation of the thin filaments. In the first part of this study, we extend these earlier findings and demonstrate that D137L mutation decreases global flexibility of α-TM and cause long-range structural rearrangements. Although much has been inferred with regard to the role of α-TM flexibility in sarcomeric control mechanisms, its relative significance in vivo is unclear. Therefore, in the second part of this study, we investigate implications of α-TM flexibility on in situ cardiac function in a novel transgenic mouse model expressing α-TM-D137L in the heart. To our knowledge, our findings are the first to demonstrate that the marked decrease in TM’s structural flexibility due to substitution of Asp 137 with Leu depresses systolic parameters of cardiac contraction and ultimately leads to a phenotype similar to dilated cardiomyopathy. At the sarcomere level, our results show that expression of α-TM-D137L in TG mouse hearts affect Ca2+ dependent activation of thin filaments while causing no change in the strongly bound cross-bridge dependent activation. Therefore we propose a mechanism that the decreased flexibility of α-TM-D137L impedes Ca2+ dependent relocation of α-TM on actin resulting in a delay in time sensitive activation and relaxation processes in cardiac muscle, which eventually leads to systolic dysfunction in TG mouse hearts. Collectively, this work sheds light on a functionally important structural characteristic of α-TM and suggests a possible association between flexibility of α-TM and cardiac disorders.en_US
dc.language.isoenen_US
dc.rightsen_US
dc.rightsCopyright 2013 Sumeyye Yaren_US
dc.subjectCardiac muscleen_US
dc.subjectFlexibilityen_US
dc.subjectTropomyosinen_US
dc.subjectThin filamenten_US
dc.subjectCardiovascular diseaseen_US
dc.subjecttransgenic mouse modelen_US
dc.subjecttropomyosin flexibilityen_US
dc.subjecttroponinen_US
dc.subjectsarcomereen_US
dc.subjectD137L, Asp137en_US
dc.titleCardiac Tropomyosin D137L Mutation Decreases Structural Flexibility to Cause Systolic Dysfunctionen_US
thesis.degree.departmentBiochemistry and Molecular Geneticsen_US
thesis.degree.disciplineBiochemistry and Molecular Geneticsen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.type.genrethesisen_US
dc.contributor.committeeMemberGaponenko, Vadimen_US
dc.contributor.committeeMemberColley, Karen J.en_US
dc.contributor.committeeMemberCaffrey, Michaelen_US
dc.contributor.committeeMemberRaychaudhuri, Pradipen_US
dc.contributor.committeeMemberKobayashi, Tomoyoshien_US
dc.type.materialtexten_US


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