Low-cost proinsulin-transferrin fusion protein in rice for treatment of diabetes

大米中的低成本胰岛素原-转铁蛋白融合蛋白用于治疗糖尿病

• 批准号: 8454380
• 负责人: Deshui Zhang
• 金额: $ 23.25万
• 依托单位: VENTRIA BIOSCIENCE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2015-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454380
• 关键词: 20 year old; Adult; Adverse effects; Affect; Animals; Biodistribution; Biological; Biological Assay; Blood; Blood Glucose; California; Cell Culture Techniques; Cell Line; Cells; Cereals; Characteristics; Chimeric Proteins; Chronic; Code; Defect; Developing Countries; Development; Diabetes Mellitus; Diagnosis; Disadvantaged; Disease; Dose; Drug Kinetics; Dyslipidemias; Embryo; Endocytosis; Enzyme-Linked Immunosorbent Assay; Epidemic; Event; Exhibits; Expenditure; Face; Financial cost; Fusion Protein Expression; Genes; Genome; Grant; Growth; Half-Life; Health; Health Care Costs; Hepatocyte; Human; Hypoglycemia; Hypoglycemic Agents; In Transferrin; In Vitro; Insulin; Insulin-Like Growth Factor I; Kidney; Life; Mammalian Cell; Measures; Medical; Metabolic; Methods; Mission; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plants; Plasma; Process; Prodrugs; Production; Productivity; Proinsulin; Proteins; Protocols documentation; Radioimmunoassay; Recombinant Fusion Proteins; Recombinants; Research; Rice; Seeds; Small Business Innovation Research Grant; Somatotropin; Subcutaneous Injections; System; TF gene; Technology; Therapeutic; Therapeutic Uses; Toxic effect; Transferrin; Transgenic Organisms; Transgenic Plants; United States National Institutes of Health; Universities; Western Blotting; base; chimeric gene; comparative efficacy; cost; cost effective; desensitization; diabetes management; diabetic; glucose production; hepatoma cell; in vivo; novel; protein purification; public health relevance; receptor; receptor binding; receptor mediated endocytosis; scale up; screening; success; trend

DESCRIPTION (provided by applicant): Diabetes has become a devastating epidemic worldwide. Insulin is commonly used as a treatment to help manage diabetes because of its ability to control blood glucose levels, and is in high demand worldwide, but it faces multiple challenges including adverse metabolic side-effects, short in vivo pharmaceutical life, and high cost. Today, millions of people continue to suffer and die from diabetes and its related conditions. Therefore, there is an urgent need to develop novel, inexpensive hypoglycemic agents to treat and arrest the fast spreading of this debilitating disease. A recombinant proinsulin-transferrin (ProINS-Tf) fusion protein was recently found to facilitate an enhanced and sustained in vivo hypoglycemic efficacy compared to insulin. While this fusion protein holds great promise as a novel hepato-specific hypoglycemic agent that can overcome some of the disadvantages of insulin, its therapeutic use is currently economically unfeasible due to low yields and high costs associated with its production in mammalian cell lines. In an effort to capture all the benefits of ProINS-Tf while lowering its supply cost, Ventria Bioscience and its collaborators at the University of Southern California are building on their respective expertise t express a ProINS-Tf chimeric protein in rice, and then assess its biological activities related to its usage as a novel hypoglycemic agent. This proposed project has three related specific aims. In Aim 1, Ventria will use its proprietary expression technology to transform rice plants with a chimeric gene construct composed of ProINS fused to Tf and will produce transgenic plants expressing ProINS-Tf. In Aim 2, Ventria will perform expression screening analysis to identify the transgenic events with the highest level expression of ProINS-Tf followed by protein purification. In Aim 3, Ventria's collaborators at the University of Southern California will confim the biological activities of ProINS-Tf through in vitro cell culture assays. The aims of these studies are to develop a novel and affordable hepatocyte prodrug for the treatment of diabetes. These studies are significant and relevant to the mission of the NIH to promote human health and reduce health care costs.

描述（由申请人提供）：糖尿病已成为一种毁灭性的流行病。由于胰岛素具有控制血糖水平的能力，它通常被用作帮助控制糖尿病的治疗方法，并且在世界范围内需求量很大，但它面临着多种挑战，包括不良的代谢副作用、体内药物寿命短和高成本。今天，数以百万计的人继续遭受并死于糖尿病及其相关疾病。因此，迫切需要开发新型、廉价的降糖药来治疗和阻止这种使人衰弱的疾病的快速传播。一种重组原胰岛素-转铁蛋白（ProINS-Tf）融合蛋白最近被发现与胰岛素相比，可以促进增强和持续的体内降糖效果。虽然这种融合蛋白作为一种新的肝特异性降糖剂具有很大的前景，可以克服胰岛素的一些缺点，但由于其在哺乳动物细胞系中生产的低产量和高成本，其治疗用途目前在经济上是不可行的。为了获得ProINS-Tf的所有好处，同时降低其供应成本，Ventria Bioscience及其南加州大学的合作者正在利用各自的专业知识，在水稻中表达ProINS-Tf嵌合蛋白，然后评估其作为新型降糖剂使用的生物活性。这个拟议的项目有三个相关的具体目标。在Aim 1中，Ventria将利用其专有的表达技术，用融合了ProINS和Tf的嵌合基因构建体转化水稻植株，并将产生表达ProINS-Tf的转基因植株。在Aim 2中，Ventria将进行表达筛选分析，确定ProINS-Tf表达水平最高的转基因事件，然后进行蛋白纯化。在第三阶段，Ventria在南加州大学的合作者将通过体外细胞培养试验确认ProINS-Tf的生物活性。这些研究的目的是开发一种新的和负担得起的治疗糖尿病的肝细胞前药。这些研究对美国国立卫生研究院促进人类健康和降低医疗保健费用的使命具有重要意义和相关性。