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

Activity-dependent energy homeostasis at the presynaptic terminal

突触前末梢活动依赖性能量稳态

基本信息

批准号：
10394964
负责人：
ROBERT B RENDEN
金额：
$ 53.91万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394964
关键词：
ATP Synthesis Pathway Acute Address Affect Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Architecture Auditory Bioenergetics Biological Assay Brain Brain Stem Buffers Cells Cellular Stress Chronic Creatine Kinase Defect Disease Disease Progression Electric Stimulation Electrophysiology (science)Energy Supply Excitatory Synapse Frequencies Functional Imaging Functional disorder Generations Glycolysis Goals Homeostasis Huntington Disease Image Impairment Intervention Knowledge Measures Mediating Metabolic Mitochondria Monitor Motivation Mus Natural regeneration Neurodegenerative Disorders Neurons Normal tissue morphology Outcome Parkinson Disease Pathologic Pathology Pathway interactions Phase Physiological Population Positioning Attribute Preparation Presynaptic Terminals Production Recycling Research Resolution Respiration Rodent Role Route Shapes Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic Time Tissues Whole-Cell Recordings Work age related base calcium uniporter functional restoration healthspan imaging probe insight mitochondrial dysfunction nervous system disorder neuron loss neurotransmission normal aging novel strategies presynaptic repaired response synaptic function transmission process uptake

项目摘要

This work is relevant to both normal aging and pathologies like Alzheimer’s disease, where brain function is impaired due to defective mitochondrial respiration and loss of cellular energy. The long-term goal of this project is to ameliorate neurotransmission defects due to mitochondrial dysfunction, as a way to stop disease progression to later degenerative stages, increasing healthspan in populations increasingly subject to age- related neurological diseases. Fundamental mechanisms underlying the bioenergetics of synaptic function in normal tissue must be resolved first, to cure these diseases. Our goals in this project are two-fold. First, the extent to which mitochondrial Ca2+ uptake facilitates ATP production in response to activity will be defined. Second, the extent that compensatory strategies are utilized at the presynaptic terminal to delay energy loss will be determined when mitochondrial function is impaired. Results from this project will provide clear mechanistic insight into the Ca2+-buffering and ATP-producing roles of synaptic mitochondria, an essential first step that is currently unclear. The PI has developed several novel approaches that allow us to dissect the bioenergetic strategies used to support transmission at the mouse calyx of Held, using a combination of electrophysiology, Ca2+ imaging, and ATP imaging. In contrast to small conventional synapses, giant ‘calyx-like’ excitatory synapses in the rodent auditory brainstem allow direct whole-cell recordings from the presynaptic terminal. This experimental accessibility permits manipulation of presynaptic [Ca2+] and [ATP], making it possible to dissect the interdependent Ca2+-buffering and energy-supporting roles of synaptic mitochondria. In the first Specific Aim, the extent that the mitochondrial calcium uniporter (MCU) facilitates mitochondrial respiration and ATP homeostasis following synaptic activity will be determined. The second Specific Aim will dissect the importance of mitochondrial Ca2+ uptake versus facilitated respiration on synaptic transmission and presynaptic short-term plasticity. Namely, is the MCU more important for Ca2+ buffering or ATP homeostasis at the synapse? In Specific Aim three, the consequence of metabolic switching between glycolysis and mitochondrial respiration in support of transmission will be examined in normal synapses, and in cases where MCU function is acutely or chronically impaired. This project will provide a detailed understanding of the range of metabolic strategies that are employed by synapses to support synaptic transmission in physiological and pathological settings. This knowledge will identify viable routes of intervention for restoring function to energy-deficient synapses that can be leveraged therapeutically to alleviate disease-related synaptic dysfunction.

这项工作与正常的衰老和像阿尔茨海默病这样的疾病有关，在这种疾病中，大脑功能是不正常的