Zhonglin Chai

Personal Information
Title Research Leader
Expertise Nephropathy
Institution Baker IDI
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Grants/SubContracts 1
Progress Reports 1
Publications 2
Protocols 0
Committees 2

A potential role of CDA1 in regulating inflammatory pathway in diabetic complications
We have previously shown that Cell Division Autoantigen 1 (CDA1) synergistically enhance TGF-ß signalling and plays an important role in diabetic nephropathy (DN) and diabetes associated atherosclerosis (DAA), with a focus on profibrotic effect. Our recent preliminary data showed that CDA1 also affected TNF-a/NFkB in the inflammation pathway, which is supported by a recent report that CDA1, also known as TSPYL2, interacts with SIRT6. SIRT6 is a histone H3 deacetylase, which was shown to directly interact with NFkB RelA/p65, and deacetylates histone H3 in the chromatin of target genes, thus inhibiting the target gene expression and terminating the signaling. TGF-ß is recently shown to induce SIRT6 expression and promote myofibroblast differentiation in human bronchial epithelial cells (HBEC), which was inhibited by overexpression of SIRT6. We hypothesize that CDA1 acts as sequester of SIRT6 via direct interaction to facilitate the activated NFkB and/or TGF-ß-activated signaling molecules to regulate their target genes. Therefore, we predict that when CDA1 is deficient or absent, SIRT6 will be recruited by these signalling molecules to their target genes where SIRT6 can deacetylate the chromatin histone H3, and inhibit the expression of the target genes, thus attenuating the signalling of NFkB mediated inflammatory and/or TGF-ß activated profibrotic pathways. We have recently generated an unique CDA1 KO mouse strain and adenoviral as well as retroviral constructs to overexpress CDA1 or to express shRNA to knockdown CDA1 in cells. These will allow us to carry out pilot experiments to examine the putative relationship between CDA1 and SIRT6, and their role in regulating inflammation and fibrosis in diabetic complications such as DN. We propose to investigate the CDA1/SIRT6 interaction in NFkB mediated inflammation and TGF-ß mediated profibrotic pathways. The specific aims are: 1. To investigate TGF-ß induced co-expression of SIRT6 and CDA1 in renal and vascular cells. 2. To determine whether CDA1 inhibits the SIRT6 mediated histone H3 deacetylation in target genes of NFkB and/or TGF-ß. 3. To determine histone H3 acetylation status in MCP1, VCAM-1, CTGF, collagens I and III genes in kidney from control and diabetic WT and CDA1 KO mice. We predict that the proposed studies will generate experimental data for us to further understand how CDA1 acts to exhibit its pathological role in the diabetic complications and provide potential targets related to CDA1 pathway for exploration of therapeutic strategies to deal with these conditions.

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Year: 2018; Items: 2

Diabetes Reduces Severity of Aortic Aneurysms Depending on the Presence of Cell Division Autoantigen 1 (CDA1).
Li J, Huynh P, Dai A, Wu T, Tu Y, Chow B, Kiriazis H, Du XJ, Bach LA, Wilkinson-Berka JL, Biros E, Walker P, Nataatmadja M, West M, Golledge J, Allen TJ, Cooper ME, Chai Z
Diabetes, 2018
Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy.
Chai Z, Wu T, Dai A, Huynh P, Koentgen F, Krippner G, Ren S, Cooper ME
Diabetes, 2018
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