Regulated Protein Degradation

调节蛋白质降解

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该研究计划的广泛长期目标是开发一般方法有条件地调节蛋白质分子水平的蛋白质功能，而不是通过靶向编码蛋白质的DNA或mRNA前体。这些实验方法高度针对靶向蛋白的特异可渗透的小分子。目标是设计称为不稳定的小蛋白质域在哺乳动物细胞中表达时会迅速降解的结构域。破坏稳定的不稳定域名忠实地授予合作蛋白与这些小领域融合的蛋白质，使研究人员能够可以预见，可以控制任何利益蛋白质的水平。该研究计划的一个具体目的将提供新的不稳定领域，这些领域是从人蛋白中得出的，并受FDA的调节批准的药物。这项研究的第二个目的是开发一种使稳定域的新方法调节人类细胞的治疗有用的细胞因子和激素的分泌。第三个目标这项研究是开发一种新方法，以针对由仅当整个融合蛋白是通过其同源配体稳定。第四目标建立在生物物理学的基础上破坏稳定的域，以开发新的基因编码生物传感器进行细胞内第二 Messenger分析物。目前缺乏安全有效的方法来调节表达和基于基因的治疗剂的生物学活性严重限制了疾病的数量和类型医师和科学家可以考虑使用细胞和基因治疗的靶向。新法规诸如安全有效的不稳定领域之类的方法将大大扩展可以通过细胞和基因治疗来治疗的疾病宇宙用于治疗人类疾病的新领域无法使用现有方法解决。