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 据推测，路易体疾病涉及 α-突触核蛋白聚集体通过中枢神经轴的扩散，其中 脑神经 I（初级嗅神经）和 X（迷走背神经）是最可能的外周进入点。嗅觉 迷走神经背侧神经是无髓鞘的，许多神经元群最容易受到α-突触核蛋白病的影响（例如， 黑质纹状体传出神经）。基于这些观察，无髓鞘神经元被假设为选择性脆弱的 路易病理学，但这个想法在过去二十年里基本上被忽视了。结果，之间的关系 髓鞘形成的程度和对α-突触核蛋白病的抵抗力仍然知之甚少。髓鞘形成的过程是 已知在神经发育过程中受到小胶质细胞的控制，但这种联系仍然有待探索 路易体疾病。为了填补这些空白，我们将利用我们新的性别分层边缘系统α-突触核蛋白病体内模型， 在一系列针对 R15 机制进行适当调整并专门为博士、药学博士和 杜肯大学药学院本科生。将检验以下中心假设 采用全因子实验设计：髓鞘形成与抵抗边缘 α-突触核蛋白病的恢复力有关，并且 由小胶质细胞/巨噬细胞修饰。 在目标 1 中，我们的团队将测试以下子假设：嗅球投射纤维中的髓鞘形成标记， 例如球内前连合和外侧嗅束，与行为、组织学、 以及预制原纤维输注小鼠的生化疾病相关结果。在目标 2 中，我们将检验以下子假设： 髓鞘形成不足或脱髓鞘会在组织学和生化水平上放大边缘 α-突触核蛋白病， 使行为缺陷恶化。在这个目标中，髓磷脂碱性蛋白（MBP）杂合的小鼠将被注射预先形成的 嗅球中的原纤维，因为这些小鼠表现出微妙的髓鞘形成不足相关的缺陷，但没有缩短寿命或 严重的行为缺陷。一组单独的原纤维注入小鼠将在饮食中喂食铜螯合剂铜宗，如下所示 已知该化合物可使前连合和侧嗅束脱髓鞘。在目标 3 中，我们将测试 小胶质细胞/巨噬细胞改善衰老小鼠的髓鞘形成并缓和边缘 α-突触核蛋白病的子假设。这 CSF1R 拮抗剂 PLX5622 将被喂给注入原纤维的衰老小鼠，以消耗骨髓来源的脑细胞。这种饮食会 随后在一组中停止使用 PLX5622，以恢复衰老的小胶质细胞生态位。我们期望 小胶质细胞/巨噬细胞耗竭会恶化髓鞘质状况和路易体病相关的结果，而 小胶质细胞/巨噬细胞的重新增殖将改善这些措施。所提出的技术方法可以通过以下方式完成 杜肯大学的博士、药学博士和本科生。我实验室的学生已获得 19 篇论文的第一作者身份， 包括 4 篇本科或药学博士学位论文。学生作为第一作者。 无论结果如何，拟议的工作都将揭示髓鞘形成之间的潜在联系 和路易相关的病理学，而学生将接受有关生物医学研究的进行和传播的培训 边缘路易体病的临床前动物模型。