权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

R21: Acidic Nanoparticles for Restoration of Autophagy in Age-associated NAFLD

R21：酸性纳米颗粒用于恢复年龄相关性 NAFLD 中的自噬

基本信息

批准号：
9902306
负责人：
MARK W. GRINSTAFF
金额：
$ 20.06万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902306
关键词：
Acidity Acids Action Research Address Age Autophagocytosis Autophagosome Biological Assay Biology Biomedical Engineering Butylene Glycols Cell physiology Cells Cellular Metabolic Process Chronic Collaborations Data Development Diabetes Mellitus Disease Disease model Drug Metabolic Detoxication Elderly Ensure Environment Evaluation Experimental Designs Exposure to Failure Fatty Acids Functional disorder Future Glycolates HepG2 Hepatic Hepatocyte Impairment In Vitro Kinetics Lactic acid Length Libraries Light Lipids Liver Lysosomes Metabolic Modeling Molecular Nanotechnology Normal Range Obesity Organelles Palmitates Pharmacology Polyesters Polymer Chemistry Polymers Process Proteins Quality Control Regulation Risk Factors Role Safety Scientist Stimulus Structure Structure of beta Cell of islet Succinic Acids System Technology base efficacy study ethylene glycol experimental study improved improved functioning in vivo insulin secretion insulinoma middle age mouse model nanoparticle non-alcoholic fatty liver disease novel novel therapeutics pharmacokinetics and pharmacodynamics restoration screening spatiotemporal tool

项目摘要

ABSTRACT This exploratory R21 proposal describes two novel nanotechnologies for acidification of the lysosome and for restoration of autophagic flux. Autophagy, the intracellular process by which proteins and organelles are degraded, requires an acidic lysosome. Failure to acidify the lysosomal compartment affords accumulation of autophagosomes, lipids, and associated undigested content. Impaired lysosomal acidification and reduced autophagic flux are central to non-alcoholic fatty liver disease (NAFLD). NAFLD occurs primarily among the middle-aged and the elderly given that the risk factors for its development increase with advancing age. Current pharmacological and molecular tools are able to reduce lysosomal acidity (increase pH); however, no tools exist to increase lysosomal acidity (decrease pH). Key to our advance is the use of lysosomal accumulating nanoparticles (NPs) that release acid to lower the local pH. Specifically, we propose two new NP technologies to increase lysosomal acidity. The first is a stimuli-responsive NP that acidifies its local environment upon exposure to light (i.e., light activated acid nanoparticle, light-acNP). The second NP responds to the pH of a dysfunctional lysosome (5.7 - 6) to release acid further lowering the pH to a healthy/normal value (4 - 5). These pH-activated acid nanoparticles (pH-acNPs) are polyester-based NPs composed of a potent diacid, tetrafluorosuccinic acid (TFSA), to further lower the pH upon NP degradation. We hypothesize that upon accumulation in lysosomes, the acNPs will release acid through light activation or pH-activation and thereby restore lysosomal acidity and autophagic flux quickly. Further, we hypothesize that the extent of restoration will depend on the length of light exposure and the amount of TFSA in the polymer, respectively. Importantly, substantial preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise (nanotechnology, polymer chemistry, cell metabolism, and autophagy) are in place to address these hypotheses. The specific aims of this two-year proposal are: Aim 1. Evaluate lysosome-targeted acNPs that activate with light (light-acNPs); and, Aim 2. Synthesize and evaluate lysosome-targeted acNPs that activate at pH 6 (pH-acNPs). Successful completion of the proposal will provide two new tools for scientists, clinicians, and biomedical engineers to study autophagy biology to facilitate agent screening and mechanism(s) of action. From a nanotechnology perspective, new nanoparticle compositions and functions will be identified as well as a means to control a key cellular process via a nanoparticle. Finally, these results would support further evaluation of the acNPs in in vivo murine models to include safety, PK/PD, and efficacy studies as part of a future R01 proposal focused on NAFLD.

摘要