Fellowship for Lefta: Contribution of the Circadian Clock Gene, Bmal1, in the Development of Dilated Cardiomyopathy

  • Esser, Karyn (PI)
  • Lefta, Mellani (CoI)

Grants and Contracts Details


E~sruption of circadian rhythre, such as occur with shift work, sleep deprivaton,- sleep spnea or jet lag, has been associated with increased incidence of cardiovascular disease. Thta fromour lab show that toss of the c'rcedian gene BiTell is associated w itli reduced ejection fraction arid increased left ventricular internal dianater, suggestive of dilated csrdion'~opathy (0CM). Consistentwith the functional data, electron nicroscopy deta show that the structural architecture of sarcoreres is coropronised. I propose that a dysfuncdonal cardion'yocyte molecular clock, resuting from either gerniine or cardiac-specific loss of Brratl leads to oxidative modifications and iaoformshfts in the sarcorrertc proteins thin and riyosin heavy chain (MHC), which in turn star cardiorfl'ocyte nechanical function and lead to 0CM. Specific Aim I will test the hypothesis that loss of Snail leeds to rrachanical dysfunction through isoforrnshfta and oxidation of titin and 1.4-IC. This rrechanical dysfuncion underlies the 0CM seen in the gerniine Snail Igiockout (Strati-I-I nodel. f~asurea will include him end 1.4-IC isoform conpostion and otidation status. ~`ocardial stiffness and contractile properties at three separate ages. The results w ill deternine whether systenic loss of Snail results in progressive changes in n'mchsnicel function, titin end 1.1-IC isoform expression and ox'dation. Specific Aim 2w ii test the hypothesis that cardiac-specfic deletion of Brratl wilt result in csrdio~'ocyte nolecular clock dysfunction, twill use (toted Smell-f- nice
Effective start/end date7/1/106/30/12


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