FASEB SRC: From Unfolded Proteins in the Endoplasmic Reticulum to Disease

FASEB SRC：从内质网中未折叠的蛋白质到疾病

基本信息

批准号：
8528302
负责人：
Erik L. Snapp
金额：
$ 0.5万
依托单位：
FEDERATION OF AMER SOC FOR EXPER BIOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-04 至 2014-06-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528302
关键词：
Address Affect Age Aging Aging-Related Process Alzheimer&apos s Disease Amino Acid Sequence Apoptotic Area Basic Science Biochemical Biochemistry Biological Biology Cardiovascular Diseases Cell physiology Cell surface Cells Cellular Stress Cellular biology Cessation of life Clinical Collection Communicable Diseases Coupled Cystic Fibrosis Data Defect Degradation Pathway Development Diabetes Mellitus Diagnosis Discipline Disease Dislocations Educational workshop Endoplasmic Reticulum Ensure Etiology Eukaryotic Cell Event Failure Financial Support Funding Future Gene Expression Gene Mutation Genetic Genetic Translation Goals Guanabenz Health Heart Diseases Heat shock proteins Hereditary Disease Homeostasis Human In Vitro Lead Malignant Neoplasms Medicine Metabolic Diseases Metabolism Minority Molecular Molecular Chaperones Molecular Conformation Mutation Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Plasma Cells Post-Translational Protein Processing Postdoctoral Fellow Prevention Process Protein Biosynthesis Protein Secretion Protein translocation Proteins Quality Control Reagent Recruitment Activity Regulation Reporting Research Research Personnel Rivers Role Scientist Series Signal Pathway Signal Transduction Site Stress Structure Structure of beta Cell of islet Students System Therapeutic Time Training Virus Diseases Woman Work base biological adaptation to stress cell type design endoplasmic reticulum stress experience human disease hypercholesterolemia inhibitor/antagonist insight interest loss of function meetings next generation normal aging novel novel therapeutic intervention polypeptide posters prevent programs protein degradation protein expression protein folding protein misfolding public health relevance response secretory protein small molecule stress protein success symposium tauroursodeoxycholic acid therapy development trafficking

Address Affect Age Aging Aging-Related Process Alzheimer&apos s Disease Amino Acid Sequence Apoptotic Area Basic Science Biochemical Biochemistry Biological Biology Cardiovascular Diseases Cell physiology Cell surface Cells Cellular Stress Cellular biology Cessation of life Clinical Collection Communicable Diseases Coupled Cystic Fibrosis Data Defect Degradation Pathway Development Diabetes Mellitus Diagnosis Discipline Disease Dislocations Educational workshop Endoplasmic Reticulum Ensure Etiology Eukaryotic Cell Event Failure Financial Support Funding Future Gene Expression Gene Mutation Genetic Genetic Translation Goals Guanabenz Health Heart Diseases Heat shock proteins Hereditary Disease Homeostasis Human In Vitro Lead Malignant Neoplasms Medicine Metabolic Diseases Metabolism Minority Molecular Molecular Chaperones Molecular Conformation Mutation Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Plasma Cells Post-Translational Protein Processing Postdoctoral Fellow Prevention Process Protein Biosynthesis Protein Secretion Protein translocation Proteins Quality Control Reagent Recruitment Activity Regulation Reporting Research Research Personnel Rivers Role Scientist Series Signal Pathway Signal Transduction Site Stress Structure Structure of beta Cell of islet Students System Therapeutic Time Training Virus Diseases Woman Work base biological adaptation to stress cell type design endoplasmic reticulum stress experience human disease hypercholesterolemia inhibitor/antagonist insight interest loss of function meetings next generation normal aging novel novel therapeutic intervention polypeptide posters prevent programs protein degradation protein expression protein folding protein misfolding public health relevance response secretory protein small molecule stress protein success symposium tauroursodeoxycholic acid therapy development trafficking

展开

项目摘要

DESCRIPTION (provided by applicant): In eukaryotic cells, proteins destined for the cell surface or for the external milieu are first translocated into the endoplasmic reticulum (ER) where initial protein folding and modifications occur that are essential for the protein to attain ts appropriate functional conformation prior to transit to the cell surface. It has long been known that mutations in the primary amino acid sequence can cause protein misfolding and contribute to disease pathogenesis. However, it is now becoming evident that in many cases disease states are not simply a result of protein loss of function, but rather frequently involve cellular processes that accommodate protein misfolding. Cells adapt to the accumulation of misfolded proteins in the ER by regulating several fundamental cellular processes including gene expression, mRNA translation, and protein degradation. We have now experienced significant breakthroughs in our understanding of how cells coordinate these adaptive responses. If adaptation is not adequate, cells enter an apoptotic death pathway. Recent studies reveal that protein misfolding results not only from gene mutations but also arises as a consequence of a variety of environmental insults including but not limited to altered metabolism, viral infection, oxidative stress, and hypercholesterolemia, as well as the altered ability to deal with these conditions that often occur during aging. Finally, many highly differentiated cell types, such as pancreatic beta cells and plasma cells, require signaling pathways to properly coordinate protein expression and secretion with the ER protein folding capacity. As we understand more about the adaptive and apoptotic responses to protein misfolding in the ER, it is evident that these events contribute to the pathology of numerous disease states. This conference will focus on recent advances in our understanding of the complexities of protein biosynthesis, folding, degradation, and cellular responses to the accumulation of misfolded proteins in the early secretory pathway as discovered through novel genetic, biochemical, and cell biological approaches. In addition, it will highlight studies on a broad collection of diseases that are caused by protein folding disorders and recent advances in approaches to prevent or correct misfolding. Identifying the mechanisms by which cells adapt and succumb to protein folding defects and the development of therapeutically useful inhibitors or activators of these processes are likely to have a tremendous impact on a variety of diseases including Alzheimer's disease, cardiovascular disease, diabetes, infectious diseases, cancer, and other diseases associated with the normal aging process.

描述（由申请人提供）：在真核细胞中，首先将原始针对细胞表面或外部环境的蛋白质转移到内质网中（ER），其中初始蛋白质折叠和修饰是蛋白质在转移到细胞表面之前适用于TS适当功能构象所必需的。长期以来，众所周知，原发性氨基酸序列中的突变会导致蛋白质错误折叠并导致疾病发病机理。但是，现在越来越明显的是，在许多情况下，疾病状态不仅是蛋白质功能丧失的结果，而且经常涉及可容纳蛋白质错误折叠的细胞过程。细胞通过调节几种基本细胞过程，包括基因表达，mRNA翻译和蛋白质降解，适应ER中错误折叠蛋白的积累。现在，我们对细胞如何协调这些适应性反应的理解经历了重大突破。如果适应不足，细胞会进入凋亡的死亡途径。最近的研究表明，由于多种环境损伤，包括但不限于代谢，病毒感染，氧化应激和高胆固醇血症，以及应对衰老期间经常发生的这些疾病的能力改变，蛋白质错误折叠的结果不仅来自基因突变，而且还引起了蛋白质的折叠结果。最后，许多高度分化的细胞类型，例如胰腺β细胞和浆细胞，都需要信号通路才能与ER蛋白质折叠能力正确协调蛋白质表达和分泌。随着我们对ER中蛋白质错误折叠的适应性和凋亡反应的更多了解，很明显，这些事件有助于众多疾病状态的病理。这次会议将重点介绍我们对蛋白质生物合成，折叠，降解和细胞反应对错误折叠蛋白在早期分泌途径中积累的积累的复杂性的最新进展，这些反应是通过新型遗传，生物化学和细胞生物学方法发现的。此外，它将强调有关蛋白质折叠障碍引起的广泛疾病的研究以及预防或纠正错误折叠的方法的最新进展。确定细胞适应和屈服于蛋白质折叠缺陷的机制以及这些过程的治疗有用的抑制剂或激活剂的发展可能会对多种疾病产生巨大影响，包括各种疾病，包括阿尔茨海默氏病，心血管疾病，心血管疾病，糖尿病，糖尿病，糖尿病，感染性疾病，感染性疾病，癌症和其他与其他正常疾病有关。