Myelination and Resilience Against Limbic Alpha-Synucleinopathy

髓鞘形成和对边缘阿尔法突触核蛋白病的抵抗力

• 批准号: 10578480
• 负责人: Rehana Khan Leak
• 金额: $ 44.75万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578480
• 关键词: 3-nitrotyrosine; Academic Research Enhancement Awards; Address; Affect; Age-Months; Aging; Amygdaloid structure; Anhedonia; Animal Model; Anosmia; Anterior; Authorship; Axon; Behavior; Behavioral; Biochemical; Biomedical Research; Brain; Brain Diseases; CSF1R gene; Cell Nucleus; Cells; Chelating Agents; Clinical; Constipation; Copper; Cuprizone; Demyelinations; Diet; Disease; Disease Outcome; Doctor of Philosophy; Dorsal; Drug Targeting; Electron Microscopy; Evoked Potentials; Experimental Designs; Fast Blue; Female; Fiber; Genetic; Glutathione Disulfide; Heterozygote; Hippocampus (Brain); Histologic; Human; Individual; Infusion procedures; Interneurons; Lateral; Lewy Bodies; Lewy Body Disease; Lewy body pathology; Lewy neurites; Light; Link; Longevity; Malondialdehyde; Measures; Microglia; Mission; Modeling; Motor; Mus; Myelin; Myelin Associated Glycoprotein; Myelin Basic Proteins; Myelin Sheath; Myelogenous; Nerve; Neuraxis; Neurofilament-H; Neurons; Odors; Olfactory Nerve; Olfactory Pathways; Olfactory tract; Oligodendroglia; Outcome; Oxidative Stress; Paper; Parkinson Disease; Pathology; Peripheral; Pharmacy Schools; Positioning Attribute; Precipitation; Preclinical Testing; Process; Proteins; Proteolipids; Reporting; Research; Rhinencephalon structure; Route; Series; Stimulus; Students; Symptoms; System; Testing; Training; Triton; Ubiquitin; United States National Institutes of Health; Universities; Variant; Wild Type Mouse; Withdrawal; Woman; Work; age related; alpha synuclein; antagonist; anterior commissure; base; brain cell; brain tissue; cohort; design; dopaminergic neuron; entorhinal cortex; experimental study; gastrointestinal system; habituation; improved; in vivo Model; macrophage; male; men; mouse model; myelination; neurodevelopment; olfactory bulb; olfactory nuclei; oligodendrocyte-myelin glycoprotein; piriform cortex; pre-clinical; protein aggregation; protein biomarkers; proteostasis; resilience; senescence; sex; synucleinopathy; theories; trend; undergraduate student; white matter

Abstract Lewy body disorders are hypothesized to involve the spread of a-synuclein aggregates through the central neuraxis, with cranial nerves I (primary olfactory nerve) and X (dorsal vagal nerve) as the most likely peripheral entry points. The olfactory and dorsal vagal nerves are unmyelinated, as are many of the neuronal groups most vulnerable to a-synucleinopathy (e.g., nigrostriatal efferents). Based on these observations, unmyelinated neurons were hypothesized to be selectively vulnerable to Lewy pathology, but this idea was largely overlooked for the last two decades. As a result, the relationship between the degree of myelination and resilience against a-synucleinopathy is still poorly understood. The process of myelination is known to lie under the control of microglial cells in neurodevelopment, but this link also remains open for exploration in Lewy body disorders. To fill these gaps, we will leverage our new sex-stratified, in vivo model of limbic a-synucleinopathy, in a series of studies appropriately scaled for the R15 mechanism and specifically designed for Ph.D., Pharm.D., and undergraduate students in the School of Pharmacy at Duquesne University. The following central hypothesis will be tested with a full-factorial experimental design: Myelination is linked to resilience against limbic α-synucleinopathy and is modified by microglia/macrophages. In Aim 1, our team will test the subhypothesis that markers of myelination in projection fibers of the olfactory bulb, such as the intrabulbar anterior commissure and lateral olfactory tracts, are inversely correlated with behavioral, histological, and biochemical disease-related outcomes in preformed fibril-infused mice. In Aim 2, we will test the subhypothesis that hypomyelination or demyelination amplifies limbic α-synucleinopathy at the histological and biochemical levels and worsens behavior deficits. In this Aim, mice heterozygous for myelin basic protein (MBP) will be infused with preformed fibrils in the olfactory bulb, as these mice display subtle hypomyelination-related deficits without shortened lifespans or severe behavior deficits. A separate cohort of fibril-infused mice will be fed the copper-chelator cuprizone in the diet, as this compound is known to demyelinate the anterior commissure and lateral olfactory tracts. In Aim 3, we will test the subhypothesis that microglia/macrophages improve myelination and temper limbic α-synucleinopathy in aging mice. The CSF1R antagonist PLX5622 will be fed to fibril-infused, aging mice to deplete brain cells of myeloid origin. This diet will be followed by PLX5622 withdrawal in one cohort to rejuvenate the aging microglial niche. We expect that microglial/macrophage depletion will worsen myelin condition and Lewy body disease-related outcomes, whereas microglial/macrophage repopulation will improve those measures. The proposed technical approaches can be completed by Ph.D., Pharm.D., and undergraduate students at Duquesne. Students in my lab have earned first-authorship on 19 papers, including 4 papers with undergraduate or Pharm.D. students as first authors. Regardless of the direction of the outcomes, the proposed work will shed light on the potential link between myelination and Lewy-related pathologies, while students will be trained in the conduct and dissemination of biomedical research on preclinical animal models of limbic Lewy body disease.

抽象的 假设Lewy体型疾病涉及A-突触核蛋白骨料通过中央神经毒素的扩散，并且 颅神经I（原发性嗅觉神经）和X（背迷走神经）是最有可能的外围入口点。嗅觉 并且背部迷走神经是不髓神经的，许多最容易受到A-突触核疾病的神经元组也是如此（例如， 黑质效率）。基于这些观察结果，假设无髓神经元有选择性易受伤害 对于路易（Lewy）的病理学，这一想法在过去的二十年中很大程度上被忽略了。结果， 对A-核疾病的髓鞘性和韧性程度仍然很差。髓鞘的过程是 已知会位于神经发育中小胶质细胞的控制之下，但此链接在 路易的身体疾病。为了填补这些空白，我们将利用我们新的性别分层的在边缘A-核酸的体内模型， 在一系列研究中，适当地缩放了R15机制，专门为博士学位而设计，Pharm.D。和 杜肯大学药学院的本科生。将测试以下中央假设 采用全因实验设计：髓鞘化与对边缘α-突触核病的弹性有关，IS 通过小胶质细胞/巨噬细胞修饰。 在AIM 1中，我们的团队将测试以下亚物种，即在嗅球的投影纤维中的髓鞘形成标记， 例如纤维内的前组成和侧向嗅觉，与行为，组织学， 和预制的原纤维注入的小鼠中与生化疾病相关的结果。在AIM 2中，我们将测试亚类假设 在组织学和生化水平以及 恶化行为定义。在此目的中，髓磷脂碱性蛋白（MBP）的杂合子将被注入预先形成 嗅球中的原纤维，因为这些小鼠表现出微妙的低切率相关的微妙定义，而没有寿命缩短或 严重的行为定义。单独的纤维注入纤维小鼠的同类将在饮食中喂食铜吉尔蛋白杯 已知该化合物可以脱髓鞘前部组成和侧向嗅水区。在AIM 3中，我们将测试 小胶质细胞/巨噬细胞可改善髓鞘和衰老小鼠中的α-突触核酸的亚类假设。这 CSF1R拮抗剂PLX5622将被喂食到纤维注入的，老化的小鼠中，以复制髓样起源的脑细胞。这种饮食会 其次是PLX5622在一个队列中撤回，以使老化的小胶质细胞生态位恢复活力。我们期望这一点 小胶质细胞/巨噬细胞部署将导致髓磷脂状况和与身体疾病相关的结局，而 小胶质细胞/巨噬细胞的重生将改善这些措施。建议的技术方法可以由 博士学位，Pharm.D。和Duquesne的本科生。我的实验室的学生在19篇论文中获得了第一章 包括4篇文章，有本科生或Pharm.D。学生作为第一作者。 无论结果的方向如何 和与路易相关的病理，而学生将接受有关生物医学研究的行为和传播的培训 边缘路易疾病的临床前动物模型。