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Project 4

项目4

基本信息

批准号：
8521832
负责人：
FRANKLIN Alan HAYS
金额：
$ 22.2万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8521832
关键词：
Affinity Amino Acids Animal Model Apoptosis Apoptotic Applications Grants Attenuated Binding Biological Preservation C-terminal Cell Death Cell Survival Cells Centers of Research Excellence Chemopreventive Agent Clinical Treatment Crystallization Data Diabetes Mellitus Disease Dissociation Dose Drug Delivery Systems Endoplasmic Reticulum Essential Drugs Family Future GRP78 gene Glucose Hepatocyte Heteroarotinoids Homeostasis In Vitro Inbred NOD Mice Instruction Insulin Insulin Receptor Insulin Signaling Pathway Knockout Mice Malignant neoplasm of ovary Mentors Methods Modeling Molecular Molecular Chaperones Molecular Structure Molecular Target Monitor National Institute of General Medical Sciences Non-Insulin-Dependent Diabetes Mellitus Obesity Oklahoma Pancreas Pathology Pathway interactions Peripheral Pharmaceutical Preparations Phase I Clinical Trials Play Positioning Attribute Prevention Production Protein Biosynthesis Proteins Receptor Signaling Regulation Relative (related person)Research Role Solutions Stress Stress Response Signaling Structure Testing Therapeutic Therapeutic Intervention Tissues Translations United States National Institutes of Health Yeasts attenuation base biological adaptation to stress diabetic drug development endoplasmic reticulum stress expectation flexibility human disease in vivo insight insulin signaling molecular chaperone GRP78 mouse model new therapeutic target novel overexpression polyhistidine protein degradation protein folding protein misfolding response small molecule structural biology tissue culture tool

项目摘要

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.

糖尿病是与内质网(ER)功能障碍直接相关的一系列人类疾病之一。这种功能障碍被称为“内质网应激”(ERS)，是腔内未折叠/错误折叠蛋白堆积的结果。细胞对ERS的反应受未折叠蛋白反应(UPR)的调节，会导致ERS的衰减或细胞凋亡。在2型糖尿病患者中，当胰岛β细胞处于高胰岛素分泌负荷以维持正常血糖时，常可观察到ERS导致细胞死亡。这一建议的重点是了解可溶性78 kDa葡萄糖调节蛋白(GRP78)的功能和活性，GRP78作为分子伴侣促进蛋白质在内质网管腔内的折叠。GRP78是UPR活性的主要调节者，因此在决定细胞对ERS的反应中发挥着重要作用。为了实现这一目标，我们将利用一部小说一类被称为FlexHets的小分子家族，现在已知以GRP78为靶点。AIM 1的重点是确定FlexHet抑制GRP78活性是否增强了胰岛素受体的信号和反应。目的2重点研究FlexHet与GRP78结合的分子基础，以此来了解GRP78的功能和小分子疗法的调节作用。目的3利用活体小鼠模型来确定GRP78抑制是否调节肥胖和非肥胖糖尿病小鼠的ERS反应和信号。因此，我们的方法是结合一系列的体外和体内方法，通过利用FlexHets作为靶向分子工具来抑制GRP78的功能和活性，从而建立GRP78功能的整体模型。GRP78此前已被证明在胰岛素信号转导中发挥关键作用，通过因此，目前的研究旨在了解这一观察的分子基础，并审查GRP78作为治疗干预治疗2型糖尿病的可行候选者。