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Abnormal Late Endosomal Trafficking in Frontotemporal Dementia due to Progranulin Mutation

颗粒体蛋白前体突变导致额颞叶痴呆的晚期内体运输异常

基本信息

批准号：
10002160
负责人：
Andrew Emmett Arrant
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2019-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002160
关键词：
Advisory Committees Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Award Behavior Biogenesis Biological Assay Biological Models Brain Brain region Budgets Cell membrane Cells Cellular biology Clinical Culture Media Data Development Dextrans Disease Doctor of Philosophy Electron Microscopy Eligibility Determination Environmental Risk Factor Enzymes Ethics Exercise Exhibits Foundations Frontotemporal Dementia Functional disorder Genes Genetic Models Genetic Polymorphism Goals Human Impairment Individual International Laboratories Laboratory Research Lysosomes Measures Membrane Proteins Mentors Morphology Multivesicular Body Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurology Neuronal Ceroid-Lipofuscinosis Neurons Neuropharmacology PGRN gene Pathogenesis Patients Pharmaceutical Preparations Phase Plasma Prefrontal Cortex Production Research Risk Rodent Sampling Scientist Social Behavior Testing Training Vesicle Viral Vector Writing behavior influence biomarker development environmental enrichment for laboratory animals enzyme activity exosome experience healthy aging knock-down loss of function mutation lysosomal proteins meetings novel post-doctoral training receptor internalization small hairpin RNA tenure track therapeutic target therapy development trafficking transcription factor

项目摘要

Project Summary/Abstract. Candidate: My goal is to become an independent scientist investigating endolysosomal dysfunction in neurodegenerative disease, with a focus on endosomal maturation and trafficking. My background is in neuropharmacology and mechanisms of rodent behavior, but I have recently shifted to investigating abnormal endosomal trafficking in progranulin-insufficient mice. Having received my PhD in 2012, this is my final cycle of eligibility for a K99/R00 award. My goal is to establish a laboratory to investigate endolysosomal dysfunction in multiple genetic models of frontotemporal dementia (FTD). After establishing expertise in this field, I hope to investigate models of Alzheimer’s disease and eventually begin to explore how environmental factors (ex. exercise, environmental enrichment, etc.) interact with neuronal endolysosomal function to influence behavior. Training: In addition to my primary mentor, Dr. Erik Roberson, I have assembled an advisory committee that includes experts on endolysosomal function (Dr. James Collawn) and exosome analysis (Dr. Andrew West), as well as Dr. David Standaert, the chair of our Department of Neurology with extensive postdoctoral training experience. I will present at international meetings and take courses (both external and internal to UAB) for technical training (cell biology, endosomal trafficking, and exosome analysis), professional development (lab management, budgeting, scientific writing, and the tenure process), and ethical conduct of research. Research: Loss-of-function mutations in progranulin (GRN) are a major cause of FTD, and are thought to cause FTD through progranulin haploinsufficiency. This proposal will test the hypothesis that FTD due to progranulin (GRN) mutations (FTD-GRN) is caused by endolysosomal dysfunction. We hypothesize that progranulin insufficiency impairs lysosomal activity, which disrupts late endosomal trafficking and ultimately causes FTD in humans and disrupts behavior in mice. Progranulin is critical for normal lysosomal function as complete progranulin deficiency causes a lysosomal storage disorder. In preliminary studies, we have observed elevated levels of exosome in plasma from FTD-GRN patients, as well as progranulin-insufficient (Grn+/–) mouse plasma and primary neuron culture media. In aim 1, we will test whether this enhanced exosome production reflects a shift in trafficking of multivesicular bodies (MVBs) away from lysosomal degradation and toward exosome secretion. In aim 2A we will determine if lysosomal dysfunction causes this enhanced exosome secretion and in aim 2B we will determine if this endolysosomal dysfunction causes behavior deficits in Grn+/– mice. In aim 3 we will compare levels of late endosomal/lysosomal proteins and MVB morphology in brains of FTD-GRN patients with healthy controls and Alzheimer’s disease patients to control for nonspecific effects of neurodegeneration. These studies will give me experience with primary neuronal culture, endosomal tracking analysis, shRNA gene knockdown, and exosome isolation and analysis.

项目总结/抽象。