Lipid dysregulation as a mediator of Rett syndrome disease progression

项目摘要 脂质失调正在成为神经发育障碍的一个重要组成部分，如Rett 综合征（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（MECP 2）基因，主要影响MECP 2表达嵌合体的女性 因为X染色体失活RTT的特征是在婴儿期明显正常发育，随后快速发育。 6-18个月大时运动和语言功能下降。除了神经系统的影响，RTT是 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， 脂质代谢最近的人类和动物研究强烈表明，脂质 RTT病理学和疾病进展中的代谢。令人兴奋的新的初步数据，从小鼠模型， RTT提示脂质的新作用：肠道中的脂质吸收不良。脂质对于 大脑发育因此，脂质吸收不良可能对神经发育产生有害影响。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影响。马赛克 雌性是相关的临床模型，但以前在小鼠中的研究主要集中在雄性身上 缺乏Mecp 2。因此，这项研究计划中概述的研究将使用一种已建立的小鼠。 RTT疾病进展模型，以评估脂质失调是否介导RTT疾病进展 在雌性嵌合体小鼠中使用两个特定的目的：1）评估脂质吸收不良对RTT的贡献 症状进展和2）检查脂质和基因表达失调在脑中的交叉点， RTT雌性小鼠。这项研究的结果将细化脂失调在RTT疾病中的作用 并提供新的治疗途径。PI将在世界知名的研究型大学接受培训 在赞助商Janine LaSalle博士和共同赞助商Ameer Taha博士的带领下，学习新的技能和技术， 这项拟议中的研究，包括神经发育障碍的遗传小鼠模型，单细胞 转录组学、靶向脂质组学和生物信息学数据分析和整合。这些研究技能将 允许PI建立在她研究代谢疾病发展起源的背景上， 未来在神经发育和脂质代谢的交叉点的独立研究。除了新 研究技能，PI的赞助商将指导她获得专业发展目标， 有助于PI的职业生涯作为一个独立的研究人员的轨迹：1）最大限度地发挥领导作用， 管理经验，磨练技能，建立一个包容性和多样化的研究环境，3）提高 科学沟通技巧，以及4）建立未来合作者的网络。在一起，研究和 本建议书中的培训计划将为PI作为独立研究人员的成功职业生涯做好准备。

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.