Regulated Protein Degradation

调节蛋白质降解

• 批准号: 10417637
• 负责人: THOMAS James WANDLESS
• 金额: $ 31.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417637
• 关键词: Address; Adopted; Basic Science; Biological; Biomedical Research; Biophysics; Biosensor; Cell Therapy; Cell physiology; Cells; Characteristics; Chimeric Proteins; Clinical; Communities; Complementary DNA; Cyclic AMP; DNA; Dependence; Development; Disease; Dose; Engineering; Ensure; Equilibrium; Eukaryotic Cell; FDA approved; Family; Genes; Genetic; Genetic Transcription; Goals; Hormones; Human; Ligand Binding; Ligands; Mammalian Cell; Mediating; Membrane; Metabolic; Methods; Mind; Operating System; Parasites; Patients; Peptide Hydrolases; Performance; Permeability; Pharmaceutical Preparations; Physicians; Plasmids; Positioning Attribute; Proprotein Convertases; Protein Engineering; Proteins; RNA Interference; Rana; Reagent; Regulation; Research; Research Personnel; Scientist; Second Messenger Systems; Ships; Specificity; System; T-Lymphocyte; Technology; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Uses; Virus; Work; Yeasts; base; cytokine; design; frontier; gene therapy; human disease; immunogenicity; interest; mRNA Precursor; mutant; programs; protein degradation; protein function; receptor; small molecule; success; targeted treatment; therapeutic gene; therapeutic protein; translational potential

Project Summary The broad, long-term objective of this research program is to develop general methods to conditionally regulate protein function at the level of the protein molecules rather than by targeting the DNA or mRNA precursors that encode a protein-of-interest. These experimental methods are highly specific for the targeted proteins and provide rapid and tunable control of protein function using cell- permeable small molecules. The goal is to engineer small protein domains called destabilizing domains that are rapidly degraded when expressed in mammalian cells. The instability of destabilizing domains is faithfully conferred to partner proteins fused to these small domains, allowing researchers to predictably control the levels of any protein-of-interest. One specific aim of this research program will provide new destabilizing domains that are derived from human proteins and regulated by FDA- approved drugs. A second aim of this research is to develop a new method for destabilizing domains to regulate the secretion of therapeutically useful cytokines and hormones from human cells. A third aim of this research is the development of a new method for the partner proteins regulated by the destabilizing domains to be liberated from the regulatory domain only when the entire fusion protein is stabilized by its cognate ligand. The fourth aim builds upon the biophysics underpinning the destabilizing domains to develop a new class of genetically encoded biosensors for intracellular second messenger analytes. The current lack of safe and effective methods to regulate the expression and biological activity of gene-based therapeutics seriously limits the number and types of diseases that physicians and scientists can contemplate targeting using cell and gene therapy. New regulation methods such as the destabilizing domains that are safe and effective will dramatically expand the universe of diseases that can be targeted for treatment through cell and gene therapy, thus opening new frontiers for treating human diseases that cannot be addressed using existing methods.

项目摘要 这项研究计划的广泛的长期目标是开发通用方法， 在蛋白质分子水平上有条件地调节蛋白质功能，而不是通过靶向蛋白质分子来调节蛋白质功能。 编码目标蛋白质的DNA或mRNA前体。这些实验方法具有很高的 对靶蛋白具有特异性，并使用细胞- 渗透性小分子。其目标是设计一种称为去稳定化的小蛋白质结构域 当在哺乳动物细胞中表达时快速降解的结构域。破坏稳定的不稳定性 结构域被忠实地赋予与这些小结构域融合的伴侣蛋白，使研究人员能够 可预测地控制任何感兴趣的蛋白质的水平。这项研究计划的一个具体目标是 提供新的去稳定化结构域，这些结构域源自人类蛋白质并受FDA监管， 批准的药物。本研究的第二个目的是开发一种新的方法来破坏域， 调节人细胞分泌治疗上有用的细胞因子和激素。第三个目标 这项研究的一个重要方面是开发了一种新的方法，用于研究由蛋白质调控的伴侣蛋白。 只有当整个融合蛋白被融合时，去稳定化结构域才能从调节结构域中释放出来。 由其同源配体稳定。第四个目标建立在生物物理学基础之上， 不稳定域开发一类新的遗传编码的生物传感器，用于细胞内第二 信使分析物。目前缺乏安全有效的方法来调控表达， 基因治疗的生物活性严重限制了疾病的数量和类型， 医生和科学家可以考虑使用细胞和基因疗法进行靶向治疗。新规 安全有效的去稳定域等方法将极大地扩大 可以通过细胞和基因治疗靶向治疗的疾病的宇宙，从而打开 治疗人类疾病的新领域，这些疾病无法使用现有方法解决。