Diversity Supplement: Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD

多样性补充：FTLD 丘脑皮质回路神经免疫功能障碍的单细胞分析

• 批准号: 10403045
• 负责人: Eric J Huang
• 金额: $ 9.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-01-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403045
• 关键词: Age; Aging; Autophagocytosis; Brain; Brain Pathology; Brain region; C9ORF72; Cell Nucleus; Cells; Clinical Research; Coculture Techniques; Cytoplasm; Data; Data Set; Dementia; Development Plans; Disease; Exhibits; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; GRN gene; Genes; Genetic; Goals; Grant; Homeostasis; Human; Immune; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Knockout Mice; Lead; Limbic System; Link; Longevity; Mediating; Mentors; Microglia; Molecular Profiling; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neuroimmune; Neurons; PGRN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Property; Proteins; RNA-Binding Proteins; Reporting; Research; Scientist; Synapses; Testing; Thalamic structure; TimeLine; Ubiquitin; Validation; Western Blotting; Wild Type Mouse; Work; age related; aging brain; astrogliosis; behavioral phenotyping; career; career development; cerebral atrophy; cohort; early onset; glial activation; graduate student; innovation; insight; loss of function; neuroinflammation; neuron loss; neurotoxicity; null mutation; parent grant; programs; protein TDP-43; protein aggregation; single cell analysis; transcriptome sequencing; transcriptomics

Project Summary Frontotemporal dementia (FTD) is an early onset neurodegenerative disease, and the second most common cause of dementia in patients 60 years or younger. The majority of familial FTD are caused by intronic hexanucleotide (CCCCGG) repeat expansion in chromosome 9 open reading frame 72 (C9orf72) gene and by dominant mutations in the Progranulin (GRN) gene, which account for 25% and 15% of familial FTD cases, respectively. These mutations cause haploinsufficiency in both genes and lead to abnormal protein aggregation involving RNA binding protein TDP-43 in neuronal nuclei and cytoplasm. The goal of the parent grant (R01 AA027074-03) is to test the hypothesis that loss of PGRN disrupts neuroimmune interaction in the thalamo- cortical circuit in Grn-/- mice. The purpose of this Diversity Supplement is to expand the scope of the parent grant and characterize the potential interaction of C9orf72 and progranulin in neurodegeneration. To this end, the proposed trainee, Naznin Jahan – a 4th year graduate student in the BMS Graduate Program at UCSF, has established an aging cohort of C9orf72-/-, Grn-/-, and C9orf72-/-;Grn-/- double KO (DKO) mice. The trainee’s results showed that C9orf72-/-;Grn-/- DKO mice exhibit age-dependent neuroinflammation and neuronal loss that are more pronounced than those seen in C9orf72-/- and Grn-/- mice. These findings support the intriguing hypothesis that simultaneous loss-of-function (LOF) in C9orf72 and GRN genes synergistically disrupts glial homeostasis and promote neuronal degeneration in an age dependent manner. The scope of this Diversity Supplement includes (1) to determine the transcriptomic changes regulated by C9orf72 and Grn in glia-neuron homeostasis, and (2) to expand the transcriptomic data using in situ hybridization (ISH), immunohistochemistry and Western blots. In addition, this Diversity Supplement includes a well-defined 2-year timeline, a detailed Mentoring Plan, and Individual Career Development Plan (ICDP) that will significantly enhance the candidate’s research capabilities and complete her dissertation work on the genetic interactions that cause the age dependent neurodegeneration in mice. Working within the proposed timeline, this supplement will prepare the candidate for her long-term career goal as an academic scientist in the field of neuroimmune interaction and neurodegeneration.

项目摘要 额颞痴呆（FTD）是一种早期发作神经退行性疾病，是第二常见的 60岁以下的患者痴呆症原因。大多数家庭FTD是由内含子引起的 六核苷酸（CCCCGG）在9号染色体上的重复扩展72（C9orf72）基因和通过 摄取元素（GRN）基因的主要突变，占家庭FTD病例的25％和15％ 这些突变导致基因的单倍不足，并导致异常的蛋白质聚集 涉及神经元核和细胞质中的RNA结合蛋白TDP-43。父母赠款的目标（R01 AA027074-03）是为了测试以下假设：PGRN的丧失会破坏丘脑的神经免疫相互作用 GRN - / - 小鼠中的皮质电路。这种多样性补充的目的是扩大父母的范围 授予并表征C9ORF72和prograNulin在神经退行性中的潜在相互作用。为此， 拟议的实习生Naznin Jahan是UCSF BMS研究生课程的四年级研究生 建立了C9orf72 - / - ，grn - / - 和c9orf72 - / - ; grn-/ - double double ko（dko）小鼠的老化队列。学员的结果 表明c9orf72 - / - ; grn - / - dko小鼠暴露了年龄依赖性的神经炎症和神经元丧失 比C9orf72 - / - 和grn - / - 鼠标中看到的更明显。这些发现支持有趣的假设 C9ORF72和GRN基因中的简单功能丧失（LOF）协同破坏了神经胶质稳态 并以年龄的方式促进神经元变性。这种多样性补充的范围 包括（1）确定由胶质神经元体内稳态中C9orf72和GRN调节的转录组变化， （2）使用原位杂交（ISH），免疫组织化学和西方扩展转录组数据 印迹。此外，这种多样性补充包括定义明确的2年时间表，详细的指导 计划和个人职业发展计划（ICDP）将大大增强候选人的研究 能力并完成有关导致年龄依赖的遗传相互作用的论文工作 小鼠的神经变性。在拟议的时间表中工作，该补充将为候选人做好准备 她作为神经免疫互动领域的学术科学家的长期职业目标和 神经变性。