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Sexual dimorphisms and role of cGAS-STING Pathway in T2DN rats
Diabetes and its renal complications are becoming an epidemic in the U.S. population. Diabetic kidney disease (DKD) is the leading cause of chronic renal pathology and, therefore, is the subject of major research efforts. DKD is one of the primary missions of the National Institute of Diabetes and Digestive and Kidney. Importantly, as described on the DiaComp website, diabetic complications manifest themselves differently between men and women. Understanding the molecular underpinnings of these manifestations is critical to designing tailored therapeutic approaches. This proposal is focused on sex differences in the progression of DKD. To explore the sexual dimorphisms in the development of DKD, we propose to use here type 2 diabetic nephropathy (T2DN) rats. Type 2 diabetes in T2DN rats is accompanied by renal histologic abnormalities that are characteristic of DN, similar to clinical observations in human patients. T2DN model was also successfully used to evaluate several drugs and signaling pathways supporting its use as a model of DKD. This project aims to determine phenotypic characteristics of DKD progression related to the sex difference in T2DN rats and identify potential mechanisms responsible for renal injury. Our preliminary data suggests the functional divergence between the kidney injury and DKD progression in male and female T2DN rats, similar to clinical observations in human patients. Aim 1 will further explore these functional and structural differences between male and female T2DN rats using gonadectomized animals. Furthermore, our pilot studies have revealed that the cyclic GMP -AMP synthase (cGAS) / Stimulator of interferon genes (STING) signaling pathway is differently regulated between male and female T2DN rats. Role of cGAS -STING pathway in multiple regulatory mechanisms, including renal inflammation, was recently reported, and we hypothesize that this pathway contributes towards the progression of DKD and sexual dimorphism. Therefore, aim 2 will provide mechanistic insight about potential mechanisms of sex differences in type 2 DN. A combination of in vivo and ex vivo studies will be used to address the following Specific Aims: Aim 1) To characterize the sexual dimorphisms in the progression of DKD in T2DN rats; and Aim 2) To define the contribution of the cGAS-STING signaling pathway in the progression of DKD and its contribution to sex difference.
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Sexual dimorphisms and role of cGAS-STING Pathway in T2DN rats (Staruschenko, Alexander)
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Year: 2021; Items: 1
Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats.
Spires DR, Palygin O, Levchenko V, Isaeva E, Klemens CA, Khedr S, Nikolaienko O, Kriegel AJ, Cheng X, Yeo JY, Joe B, Staruschenko A
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The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the
External Evaluation Committee
The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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