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Probing organismal proteostasis through the response to intracellular infection

通过对细胞内感染的反应探索机体蛋白质稳态

基本信息

批准号：
9353488
负责人：
Emily R Troemel
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353488
关键词：
Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animals Binding Biochemical Boxing Budgets CUL1 gene Caenorhabditis elegans Caring Cells Complex Cullin Proteins Data Defect Degenerative Disorder Degradation Pathway Disease F Box Domain Gene Expression Genes Genetic Genetic Epistasis Genetic Screening Genetic Transcription Glutamine Goals Growth Health Healthcare Healthcare Systems Homeostasis Human Huntington Disease Immune response Infection Intestines Lead Ligase Maintenance Mediating Methods Microbe Microsporidia Molecular Monitor Nematoda Neurodegenerative Disorders Outcome Parkinson Disease Pathway interactions Patient Care Patients Proteasome Inhibition Proteins Proteomics RNA Interference RNA Viruses Research Resistance Role Signal Pathway Source Stress Structure Testing Tissues Ubiquitination Up-Regulation Virus age related base coping improved innovation insight mutant novel novel strategies novel therapeutics pathogen polyglutamine pressure protein aggregate protein misfolding response stressor transcriptome sequencing ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Maintenance of protein homeostasis, or proteostasis, is critical for health. Proteostasis is perturbed in several aging-related diseases including neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases. Caring for patients with these diseases is consuming an increasing fraction of our health care budget. Strikingly, care for Alzheimer's patients alone is responsible for $226 billion in spending per year, and no treatments are available. Thus, new approaches are needed. One such approach involves leveraging the host/pathogen response to infection with intracellular microbes. Our long-term goal is to dissect the mechanisms by which host cells upregulate proteostasis pathways to cope with the increased burden of intracellular infection and replication. Closing this gap in our understanding will provide new insights about proteostasis, and could provide novel treatments for neurodegenerative diseases. Our central hypothesis is that hosts can sense the effects of intracellular infection and increase proteostasis capacity to cope with this increased burden. The objective here is to determine the mechanisms by which the nematode C. elegans upregulates ubiquitin ligase components in response to infection by a natural intracellular microbe that belongs to the microsporidia phylum. Microsporidia commonly infect all animals including humans, and can replicate to very high levels without causing overt effects on the host, likely due to host compensatory mechanisms. Our recent findings indicate that C. elegans upregulates ubiquitin ligase components in response to diverse intracellular infections including microsporidia and virus (Bakowski et al 2014). In unpublished data we have isolated mutants defective in an F-box-related gene (fbxr-1) that constitutively express these ubiquitin ligase components. fbxr-1 mutants have increased pathogen resistance, as well as greatly enhanced thermotolerance and reduced levels of aggregated proteins, indicating improved proteostasis capacity. We hypothesize that C. elegans increases transcription of Skp-Cullin-F-box (SCF) ubiquitin ligase components in order to target misfolded proteins for ubiquitination and destruction, increasing tolerance of proteotoxic insults. In Specific Aim 1 we will determine where the Cullin, as well as its upstream negative regulator FBXR-1 act to regulate thermotolerance. We also will perform structure/function analysis on the Cullin to test the hypothesis that it is part of a multi-subunit SCF ubiquitin ligase component. In Specific Aim 2 we will identify these other SCF ligase components using genetic and biochemical approaches. In Specific Aim 3 we will identify new components of the FBXR-1/Cullin pathway using RNAseq analysis, genetic epistasis, and a forward genetic screen. In Specific Aim 4 we will determine where and when FBXR-1 regulates levels of protein aggregates. This approach is innovative because it leverages the host response to obligate intracellular infection to understand how proteostasis can be improved. The proposed research is significant because it could lead to new treatments for diseases of compromised proteostasis, such as Alzheimer's disease.