Diabetes is one of a broad range of human diseases and disorders that are directly associated with endoplasmic reticulum (ER) malfunction. This malfunction is termed """"""""ER stress"""""""" (ERS) and results from the accumulation of luminal unfolded/misfolded proteins. Cellular response to ERS is regulated by the Unfolded Protein Response (UPR) and will result in either ERS attenuation or apoptosis. ERS leading to cell death is often observed in type 2 diabetes when pancreatic p-cells are placed under high insulin production loads to maintain euglycemia. This proposal is focused on understanding the function and activity of the soluble 78 kDa Glucose-Regulated protein (GRP78) that serves as a molecular chaperone to facilitate protein folding in the ER lumen. GRP78 is a master regulator of UPR activity and thus plays a significant role in determining cellular response to ERS. To accomplish this objective we will utilize a novel family of small molecules called FlexHets that are now known to target GRP78 function. The focus in AIM 1 is to determine if FlexHet inhibition of GRP78 activity enhances insulin receptor signaling and response.
AIM 2 is focused on determining the molecular basis for FlexHet binding to GRP78 as a means to understand GRP78 function and regulation by small molecule therapeutics.
AIM 3 uses in vivo mouse models to determine if GRP78 inhibition modulates ERS response and signaling in obese vs. non-obese diabetic mice. Thus, our approach is to combine a range of in vitro and in vivo methods to develop a holistic model of GRP78 function by utilizing FlexHets as a targeted molecular tool to inhibit GRP78 function and activity. GRP78 has been previously shown to play a key role in insulin signaling using heterozygous knockout mice so the current studies are aimed at understanding the molecular basis for this observation and vetting GRP78 as a viable candidate for therapeutic intervention in the treatment of type 2 diabetes.
This project investigates how a protein involved in the onset of type 2 diabetes functions at the molecular level. Through these studies we aim to gain insights into how the protien, called GRP78, functions in the diabetic state and determine if the protein is a viable target for new therapeutics in the future.
|Orock, Albert; Logan, Sreemathi; Deak, Ferenc (2018) Munc18-1 haploinsufficiency impairs learning and memory by reduced synaptic vesicular release in a model of Ohtahara syndrome. Mol Cell Neurosci 88:33-42|
|Wang, Bing; Li, Pui-Kai; Ma, Jian-Xing et al. (2018) Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage. Invest Ophthalmol Vis Sci 59:3630-3642|
|Shin, Younghwa; Moiseyev, Gennadiy; Petrukhin, Konstantin et al. (2018) A novel RPE65 inhibitor CU239 suppresses visual cycle and prevents retinal degeneration. Biochim Biophys Acta Mol Basis Dis 1864:2420-2429|
|Fu, Shuhua; Dong, Shuqian; Zhu, Meili et al. (2018) VEGF as a Trophic Factor for Müller Glia in Hypoxic Retinal Diseases. Adv Exp Med Biol 1074:473-478|
|Chen, Qian; Qiu, Fangfang; Zhou, Kelu et al. (2017) Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPAR?. Diabetes 66:1671-1682|
|Du, Mei; Martin, Ashley; Hays, Franklin et al. (2017) Serum retinol-binding protein-induced endothelial inflammation is mediated through the activation of toll-like receptor 4. Mol Vis 23:185-197|
|Malechka, Volha V; Moiseyev, Gennadiy; Takahashi, Yusuke et al. (2017) Impaired Rhodopsin Generation in the Rat Model of Diabetic Retinopathy. Am J Pathol 187:2222-2231|
|Qiu, Fangfang; Liu, Zhen; Zhou, Yueping et al. (2017) Decreased Circulating Levels of Dickkopf-1 in Patients with Exudative Age-related Macular Degeneration. Sci Rep 7:1263|
|Pearsall, Elizabeth A; Cheng, Rui; Zhou, Kelu et al. (2017) PPAR? is essential for retinal lipid metabolism and neuronal survival. BMC Biol 15:113|
|Le, Yun-Zheng (2017) VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases. Vision Res 139:108-114|
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