Neuroresilience to hyper-gravity and desiccation in tardigrade Hypsibius exemplaris

缓步动物 Hypsibius exemplaris 对超重力和干燥的神经弹性

• 批准号: 10607915
• 负责人: Molly J Kirk
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607915
• 关键词: Acetylation; Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Anatomy; Animals; Ankyrins; Behavioral; Biological Assay; Brain; Caenorhabditis elegans; Centrifugation; Chemical Synapse; Collaborations; Data; Dehydration; Dementia; Desiccation; Development; Disease; Environment; Excision; Exposure to; Force of Gravity; Freezing; Gap Junctions; Generations; Genetic Transcription; Goals; Head; Health; Homologous Gene; Hour; Human; Hydration status; Hypergravity; In Vitro; Invertebrates; Length; Maintenance; Manuals; Memory; Metabolic; Modeling; Molds; Molecular; Molecular Target; Mollies; Monitor; Morphology; Motion; Mus; Natural regeneration; Nerve Degeneration; Nervous System; Nervous System Physiology; Neurites; Neurodegenerative Disorders; Neurons; Patient-Focused Outcomes; Persons; Phenotype; Phosphorylation; Physiology; Planet Earth; Population; Predisposition; Process; Proteins; Proteome; Proteomics; Protocols documentation; RNA Interference; Recovery; Regenerative capacity; Regulation; Research; Role; Stress; Suspensions; Synapses; Synapsins; System; Testing; Therapeutic; Time; Tubulin; Up-Regulation; Visualization; Walking; Water; Work; abeta toxicity; adeno-associated viral vector; animation; aversive conditioning; cohort; density; environmental stressor; fortification; genetic regulatory protein; knock-down; long term memory; memory retention; mouse model; nervous system disorder; neural; neuroligin 1; neuronal survival; new therapeutic target; normal aging; novel; presynaptic; prevent; regenerative; resilience; response; synaptic function; system architecture; therapeutic development; transcriptome sequencing; transcriptomics

SUMMARY: The stability of neural connections (synapses) and long-term survival of neurons are critically important to human health, as many neurological and neurodegenerative disorders, including dementia, result in the loss of vital synaptic connections in the brain. These dementia disorders currently affect 28 million people worldwide, a number that will increase precipitously as our population continues to age. The proposed research will explore how synapses are maintained when faced with exposure to extreme environmental stressors with the aim of identifying translatable molecular targets to prevent synaptic loss during the normal aging process and the diseased state. To evaluate synaptic stability in the extremes, we will use an invertebrate species, the tardigrade Hypsibius exemplaris, which has the ability to survive near-complete desiccation, and which I recently found can survive extreme hyper-gravity equivalent to 500,000 times the earth’s gravity for an hour. Mechanisms by which the animal survives desiccation are relatively well understood, in that the animal forms a ‘tun,’ an inanimate state of metabolic suspension which is accompanied by gross morphological changes and the loss of nearly 99% of their water content. In contrast, the mechanisms by which these animals survive the extreme forces exerted by hyper-gravity remain wholly unexplored. Following reanimation from desiccation or return to normal gravity, animals rapidly restore coordinated walking and head motions suggesting that their nervous system remains grossly unperturbed by these phenomenal feats of extremotolerance. A critical question is how the nervous system and synaptic function remain stable under these extraordinary environmentally induced stresses. The proposed research will unveil the underpinnings of tardigrade nervous system survival by testing the hypothesis that tardigrades fortify their nervous system through the stabilization of synapses under extreme environmental insults. We will first explore anatomical changes to synapse density and morphology during desiccation and hyper-gravity by direct visualization of synapses and neurons in the nervous system (Aim 1). We will assess the functional maintenance of synapses throughout desiccation and hyper-gravity via a memory-retention paradigm (Aim 2). Finally, we will identify novel targets by monitoring the dynamic changes in the “proteome” that are triggered by extreme hyper-gravity and desiccation, analyze the functional roles of synaptic proteins via the removal of key synaptic regulatory proteins and ultimately apply our identified target molecules to analysis of an in vitro mouse model of neurodegeneration (Aim 3).

摘要：神经连接(突触)的稳定性和神经元的长期存活至关重要 对人类健康很重要，因为许多神经和神经退行性疾病，包括痴呆症， 大脑中重要的突触连接的丧失。这些痴呆症目前影响着2800万人 在世界范围内，这个数字将随着我们人口的继续老龄化而急剧增加。拟议的研究 将探索在面对极端环境应激时突触是如何保持的 识别可翻译的分子靶点以防止正常衰老过程中突触丢失的目的 以及患病的国家。为了评估极端情况下突触的稳定性，我们将使用无脊椎动物物种 有能力在接近完全干燥的情况下存活，而且我 最近发现的可以在相当于地球500,000倍重力的极端超重力下存活一小时。 动物在干燥中存活的机制相对较好地被理解，因为动物的形式 一种代谢悬浮的无生命状态，伴随着大体的形态变化。 并损失了近99%的水分。相比之下，这些动物赖以生存的机制 超重力所施加的极端力量仍然完全没有被研究过。从脱水中苏醒过来 或者回到正常的重力状态，动物迅速恢复协调行走和头部运动，这表明它们的 神经系统仍然完全不受这些极端忍耐的非凡壮举的干扰。一位批评者 问题是神经系统和突触功能如何在这些不同寻常的情况下保持稳定 环境诱导的压力。这项拟议的研究将揭示迟发性神经症的基础。 通过检验迟滞通过稳定来加强他们的神经系统的假设来进行系统生存 在极端的环境侮辱下的突触。我们将首先探索突触密度的解剖学变化 在干燥和超重力过程中通过直接可视化突触和神经元的形态 神经系统(目标1)。我们将评估突触在干燥和干燥过程中的功能维持 通过记忆保持范式实现超重力(目标2)。最后，我们将通过监测 极端超重力和干燥引发的“蛋白质组”的动态变化，分析 突触蛋白通过移除关键突触调节蛋白的功能作用并最终应用 我们确定的靶分子用于分析神经变性的体外小鼠模型(目标3)。