Grants and Contracts Details
Description
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
Status | Finished |
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Effective start/end date | 7/1/10 → 6/30/12 |
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