NIH Minority Supplement for Kerry A. Smith to GM120357

NIH 凯瑞·史密斯 (Kerry A. Smith) GM120357 少数族裔补充

• 批准号: 9899572
• 负责人: Weiping Tang
• 金额: $ 5.85万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899572
• 关键词: Adverse effects; Affect; Antibodies; Binding; Binding Sites; Biological; Biological Assay; Biology; Biotin; Cardiovascular Diseases; Cause of Death; Cells; Chemicals; Cholesterol Homeostasis; Clinical; Cross-Linking Reagents; Degradation Pathway; Family Study; Foundations; Genes; Genetic Transcription; Hyperlipidemia; Indoles; LDL Cholesterol Lipoproteins; Laboratories; Lead; Lipids; Low-Density Lipoproteins; Mediating; Metabolic; Minority; Molecular Probes; Natural Products; Organic Synthesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Play; Post-Translational Protein Processing; Proprotein Convertases; Protein Biosynthesis; Proteins; Proteomics; Reagent; Regulation; Research; Role; Subtilisins; Therapeutic; Toxic effect; Translations; Treatment Protocols; United States National Institutes of Health; analog; base; clinical development; cytotoxicity; design; human disease; hypercholesterolemia; improved; innovation; interdisciplinary approach; new therapeutic target; novel; public health relevance; small molecule; tool

ABSTRACT Cardiovascular diseases (CVD) is the number one cause of death world-wide. High levels of low density lipoprotein (LDL), clinically known as hypercholesterolemia or hyperlipidemia, are strongly associated with CVD. Although statin therapy has been very successful for many patients with hypercholesterolemia, about 20% of patients are not able to achieve target LDL levels due to the adverse effects of statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major regulatory role in cholesterol homeostasis and is a validated new therapeutic target for the treatment of hypercholesterolemia. Compounds that inhibit the action of PCSK9 can be stand-alone treatments or function as synergistic agents with statins in a hypercholesterolemia treatment regimen. It took only 12 years from the discovery of the PCSK9 gene to the approval of two antibody drugs against the secreted PCSK9 protein, which is a strong testimony for the significance and importance of PCSK9. However, the understanding of the basic biology of PCSK9 lags far behind the clinical development. This collaborative proposal from laboratories of Tang, Attie, and Li at UW- Madison is intended to study the biological mechanism and protein target of novel small molecules that can lead to selective degradation of PCSK9 protein. We will accomplish these objectives by completing three specific aims: 1) Develop sensitive assays to evaluate the potency, cytotoxicity, selectivity, and metabolic stability of novel small molecule PCSK9 modulators; 2) Elucidate the mechanism of action of our small molecule PCSK9 modulators by an iterative approach from transcription, translation, posttranslational modification and degradation, to secretion; 3) Identify the direct binding partner of our small molecule PCSK9 modulators with appropriate chemical probes, investigate the physiological function of this binding partner, and evaluate its therapeutic potential. This proposal is innovative because our small molecules target PCSK9 regulation pathways that are distinct from known biological reagents such as antibodies and known natural products, most of which down regulate the transcription of PCSK9. Based on our preliminary results, we hypothesize that our compounds regulate the stability of PCSK9 by selectively promoting the post-translational degradation of PCSK9. We proposed multiple interdisciplinary approaches to examine how our small molecules affect transcription, translation, protein processing and degradation, and the secretory pathway of PCSK9. The proposed study will yield novel small molecule tools that can change how we study lipid regulating pathways and also uncover new biological targets and pathways for treating hypercholesterolemia.

摘要