Sigma-1 receptor (Sigmar1) is a molecular chaperone protein widely expressed throughout the body. Recently, we have reported that Sigmar1 is highly expressed in the cardiomyocytes in human and mouse hearts. However, the molecular function of Sigmar1 in the heart under physiological and pathophysiological conditions remains obscure. Our preliminary study revealed that Sigmar1 activates adaptive endoplasmic reticulum stress (ER stress) pathway, an evolutionarily conserved process to maintain cellular homeostasis, and protects cardiomyocytes under stress. Although extensive studies indicate that Sigmar1 ligands elicit protective effects in the mouse model of diabetic retinopathy, Sigmar1's direct involvement in diabetes remains elusive due to the lack of tissue-specific Sigmar1 genetic mouse models. In our current postdoctoral fellowship grant application, we aim to discover the cardioprotective role of Sigmar1 in diabetic cardiomyopathy development by utilizing our newly developed unique cardiac-specific Sigmar1 knockout and transgenic mice. We will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to define the direct involvement and protective role of Sigmar1 in diabetes-induced cardiac dysfunction. We will conduct two overarching aims based on our preliminary data: i) Aim 1 will determine the hypothesis that Sigmar1 confers protection in cardiac dysfunction and adverse remodeling in streptozotocin-induced diabetic cardiomyopathy in mice, and ii) Aim 2 will test the hypothesis that Sigmar1 mediates its cardioprotective effects by activating the adaptive ER stress pathway. This study will permit us to determine the direct involvement of Sigmar1 to confer cardioprotection in diabetic mice. The proposed project will identify a novel function of a molecular chaperone protein and discover the molecular mechanism of cardioprotection with the ultimate goal of determining whether drugs targeting Sigmar1 are clinically useful for diabetic cardiomyopathy.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|