Lipid dysregulation as a mediator of Rett syndrome disease progression

脂质失调是雷特综合征疾病进展的介质

• 批准号: 10228374
• 负责人: Kari Elizabeth Neier
• 金额: $ 6.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-24 至 2022-04-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228374
• 关键词: Affect; Age; Age-Months; Animals; Astrocytes; Bile Acids; Bioinformatics; Body fat; Brain; Cell Nucleus; Cells; Characteristics; Cholesterol; Cholesterol Homeostasis; Communication; Critical Pathways; Data; Data Analyses; Data Set; Development; Dietary Fats; Digestion; Disease; Disease Progression; Environment; Exhibits; Fellowship; Female; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Hepatic; Histopathology; Human; Immune system; Immunohistochemistry; Impaired cognition; Inflammation; Intestines; Intravenous; LDL Cholesterol Lipoproteins; Language; Leadership; Learning; Life; Link; Lipids; Liver; Lung; Malabsorption Syndromes; Measures; Mediating; Mediator of activation protein; Mentors; Metabolic Diseases; Metabolism; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Mosaicism; Motor; Motor Skills; Mus; Mutate; Mutation; Neurodevelopmental Disorder; Neurologic; Neurologic Effect; Nutritional Support; Pathogenesis; Pathology; Patients; Phenocopy; Phenotype; Play; Polyunsaturated Fatty Acids; Process; Production; Protein Isoforms; Quality of life; Reporting; Research; Research Personnel; Research Training; Resolution; Rett Syndrome; Role; Sampling; Serum; Small Intestines; Small Nuclear RNA; Speech; Symptoms; Techniques; Technology; Testing; Time; Tissue-Specific Gene Expression; Training; Triglycerides; Universities; Venous; X Inactivation; absorption; career; causal variant; clinically relevant; data integration; docosahexaenoylascorbic acid; experience; gene therapy; girls; improved; infancy; insight; lipid metabolism; lipidomics; male; metabolic phenotype; mouse model; nervous system development; neurodevelopment; neuroinflammation; novel; novel therapeutics; skills; synaptic function; synaptogenesis; transcriptome sequencing; transcriptomics; uptake

PROJECT SUMMARY Lipid dysregulation is emerging as a critical component of neurodevelopmental disorders, such as Rett syndrome (RTT). RTT is an X-linked dominant disorder caused primarily by mutations in the methyl-CpG binding protein 2 (MECP2) gene, and predominantly affects females who are mosaic for MECP2 expression due to X-inactivation. RTT is characterized by apparently normal development in infancy, followed by rapid decline of motor and speech functions at 6-18 months of age. In addition to neurological effects, RTT is increasingly recognized as a multi-system disorder, affecting the lungs, intestinal tract, immune system, and lipid metabolism. Recent human and animal studies have strongly indicated a significant role for lipid metabolism in RTT pathology and disease progression. Exciting new preliminary data from a mouse model of RTT suggests a new role for lipids: lipid malabsorption in the intestinal tract. Lipids are crucial for the developing brain. Thus, lipid malabsorption could have detrimental effects on neurodevelopment. Lipid malabsorption can be corrected using nutritional therapies, presenting a potential opportunity for RTT treatment. Furthermore, our preliminary data point to lipid malabsorption as a female-specific effect. Mosaic females are the relevant clinical model, but previous studies in mice have largely focused on males completely deficient in Mecp2. The research outlined in this fellowship proposal will therefore use an established mouse model of RTT disease progression to evaluate whether lipid dysregulation mediates RTT disease progression in female mosaic mice using two specific aims: 1) evaluate the contribution of lipid malabsorption to RTT symptom progression and 2) examine the intersection of lipid and gene expression dysregulation in the brain of RTT female mice. The findings from this research will refine the role of lipid dysregulation in RTT disease progression and provide new avenues of treatment. The PI will train at a world-renowned research university under Sponsor Dr. Janine LaSalle and Co-Sponsor Dr. Ameer Taha to learn new skills and techniques to carry out this proposed research, including genetic mouse models of neurodevelopmental disorders, single-cell transcriptomics, targeted lipidomics, and bioinformatic data analysis and integration. These research skills will allow the PI to build on her background in studying the developmental origins of metabolic disease towards future independent research at the intersection of neurodevelopment and lipid metabolism. In addition to new research skills, the PI’s Sponsor will mentor her in obtaining professional development goals that will be instrumental in the PI’s trajectory towards a career as an independent researcher: 1) maximize leadership and management experience, hone skills at building an inclusive and diverse research environment, 3) improve scientific communication skills, and 4) build a network of future collaborators. Together, the research and training plan in this proposal will prepare the PI for a successful career as an independent researcher.

项目概要 脂质失调正在成为神经发育障碍的一个重要组成部分，例如 Rett 综合症（RTT）。 RTT 是一种 X 连锁显性遗传疾病，主要由甲基 CpG 突变引起 结合蛋白 2 (MECP2) 基因，主要影响 MECP2 表达镶嵌的女性 由于 X 失活。 RTT 的特点是婴儿期发育明显正常，随后是快速发育 6-18 个月大时运动和言语功能下降。除了神经系统影响外，RTT 还 越来越多地被认为是一种多系统疾病，影响肺部、肠道、免疫系统和 脂质代谢。 Recent human and animal studies have strongly indicated a significant role for lipid RTT 病理学和疾病进展中的代谢。来自小鼠模型的令人兴奋的新初步数据 RTT 表明脂质的一个新作用：肠道中的脂质吸收不良。脂质对于人体至关重要 正在发育的大脑。因此，脂质吸收不良可能对神经发育产生不利影响。脂质 吸收不良可以通过营养疗法来纠正，这为 RTT 提供了潜在的机会 治疗。此外，我们的初步数据表明脂质吸收不良是女性特有的效应。马赛克 雌性是相关的临床模型，但之前对小鼠的研究主要完全集中在雄性身上 Mecp2 缺乏。因此，本奖学金提案中概述的研究将使用已建立的小鼠 RTT 疾病进展模型以评估脂质失调是否介导 RTT 疾病进展 在雌性嵌合小鼠中使用两个特定目标：1) 评估脂质吸收不良对 RTT 的影响 症状进展，2) 检查大脑中脂质和基因表达失调的交叉点 RTT 雌性小鼠。这项研究的结果将完善脂质失调在 RTT 疾病中的作用 进展并提供新的治疗途径。 PI将在世界知名研究型大学接受培训 在赞助商 Janine LaSalle 博士和联合赞助商 Ameer Taha 博士的指导下学习新的技能和技巧 提出了这项拟议的研究，包括神经发育障碍的遗传小鼠模型、单细胞 转录组学、靶向脂质组学以及生物信息数据分析和整合。这些研究技能将 让 PI 能够以她研究代谢疾病发展起源的背景为基础， 未来在神经发育和脂质代谢交叉点的独立研究。除了新 研究技能，PI 的赞助商将指导她实现职业发展目标 在 PI 作为独立研究员的职业轨迹中发挥着重要作用：1）最大限度地发挥领导力和 管理经验，磨练建立包容性和多元化研究环境的技能，3）提高 科学沟通技巧，4) 建立未来合作者网络。一起，研究和 本提案中的培训计划将为 PI 做好独立研究员成功职业生涯的准备。