Normalizing E:I imbalance in Rett Syndrome by Modulation of Late Response Genes
通过调节晚期反应基因使 Rett 综合征中的 E:I 失衡正常化
基本信息
- 批准号:10076486
- 负责人:
- 金额:$ 8.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-04 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY AND CAREER DEVELOPMENT ABSTRACT
Rett syndrome (RTT) is a devastating neurodevelopmental disorder for which there are currently no
viable treatment strategies. The majority of RTT cases result from loss of function mutations in a transcription
factor known as methyl CpG binding protein 2 (MECP2), and knockout of Mecp2 (Mecp2-KO) results in RTT-
like phenotypes and pathologies in rodents. The brains of RTT-model mice are characterized by acquired
microcephaly, which results not from neural atrophy, but rather a reduction in synapses and the subsequent
simplification of the neuronal arbor. As such, the preclinical treatment strategies that have garnered the most
attention are those designed to normalize synaptic density, often through the replacement of late response
(LR) or direct modulation of their receptors. In this capacity RTT-mouse models are valuable tools to guide
therapeutic design; however, given the challenges associated with translating data from mice to humans, we
have recently adopted a different strategy. Using cortical and cerebellar tissue from 8 RTT patients, we
performed RNA-sequencing (seq) analysis to screen for novel points of intervention that are rooted in human
patient data, and then back-modeled relevant hits in mice. Excitingly, we identified the muscarinic acetylcholine
receptor 4 (M4) as a gene significantly decreased in RTT patients. This finding is salient, as M4-modulators
have been shown to rescue symptom domains in diseases like schizophrenia that overlap with RTT and M4-
KO mice have cognitive and social deficits similar to Mecp2-KO mice. This raises the exciting possibility that
attenuated M4 expression and signaling could be underlying cognitive and social phenotypes in RTT patients.
In Aim 1, we propose to further develop preliminary data indicating that cognitive and social phenotypes in
Mecp2-KO mice are responsive to M4 positive allosteric modulators (PAMs). In Aim 2, we propose to
conclusively link M4-signaling to RTT in patients by perform an RNA-seq analysis on autopsy samples from
patients that have been clinically diagnosed with RTT, but who do not have mutations in MECP2 (MECP2-
mutation negative). Finally, in Aim 3 we propose co-administer our M4-PAM with modulators of glutamatergic
and GABAergic signaling, to establish whether a complimentary symptom domains can be rescued.
My career goal is to become the head of a lab with a research focus on pediatric diseases of the
nervous system, and I have identified four areas of insufficient training that I propose to remedy to assist in
achieving long term success in that role. The four areas are: 1) Training in electrophysiology 2) Training next
generation sequencing analysis 3) Clinical exposure to RTT and 4) Mentor experience. To remove these
technical and conceptual barriers, I have developed a training plan that integrates formal didactic training with
hands-on mentorship, with the goal of turning these weaknesses into strengths. It is anticipated that completion
of the proposed project and training plan will place me in an ideal position to receive a tenure track faculty
position, and as such, I believe that this application is well suited for a K01 Career Development Award.
项目总结和职业发展摘要
Rett综合征(RTT)是一种破坏性的神经发育障碍,目前尚无治疗方法
可行的治疗策略。大多数RTT病例是由于转录中的功能突变丢失所致
被称为甲基CpG结合蛋白2(MECP2)的因子和MeCP2(MeCP2-KO)的敲除导致RTT-
就像啮齿动物的表型和病理一样。RTT模型小鼠的大脑以获得性
小头畸形,不是由神经萎缩引起的,而是突触减少和随后的
神经节的简化。因此,临床前治疗策略获得了最多的
注意是那些旨在使突触密度正常化的东西,通常是通过替换晚期反应来实现的
(LR)或对其受体的直接调制。在这种能力下,RTT-鼠标模型是指导
治疗设计;然而,考虑到将数据从小鼠转换为人类的相关挑战,我们
最近采取了一种不同的策略。利用8名RTT患者的皮质和小脑组织,我们
进行RNA测序(SEQ)分析以筛选植根于人类的新的干预点
患者数据,然后在小鼠身上反向模拟相关的命中。令人兴奋的是,我们发现了毒碱类的乙酰胆碱
受体4(M4)基因在RTT患者中显著降低。这一发现是显著的,因为M4-调节器
已被证明可以挽救精神分裂症等与RTT和M4重叠的疾病的症状域-
KO小鼠的认知和社会缺陷与MeCP2-KO小鼠相似。这增加了一种令人兴奋的可能性
M4表达和信号的减弱可能是RTT患者潜在的认知和社会表型。
在目标1中,我们建议进一步开发初步数据,表明认知和社会表型在
MeCP2-KO小鼠对M4阳性变构调节剂(PAM)有反应。在目标2中,我们建议
通过对来自中国的尸检样本进行RNA-SEQ分析,最终将M4信号与患者的RTT联系起来
已被临床诊断为RTT,但没有MECP2(MECP2-)突变的患者
突变阴性)。最后,在目标3中,我们建议将我们的M4-PAM与谷氨酸能调节剂联合给药
和GABA能信号,以确定是否可以挽救一个互补的症状域。
我的职业目标是成为一个实验室的负责人,专注于儿童疾病的研究
神经系统,我已经确定了四个训练不足的领域,我建议补救以帮助
在这一角色上取得长期成功。这四个领域是:1)电生理学培训2)接下来的培训
世代测序分析3)临床接触RTT和4)导师经验。要删除这些文件,请执行以下操作
技术和概念障碍,我已经制定了一项培训计划,将正式的说教培训与
亲力亲为的指导,目标是将这些弱点转化为优势。预计该项目的完成
拟议的项目和培训计划将使我处于获得终身教职的理想位置
因此,我相信这份申请非常适合K01职业发展奖。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rocco George Gogliotti其他文献
Rocco George Gogliotti的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Rocco George Gogliotti', 18)}}的其他基金
miRNA site-blocking ASOs as MeCP2 targeted therapeutics
miRNA 位点阻断 ASO 作为 MeCP2 靶向治疗
- 批准号:
10648126 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Normalizing E:I imbalance in Rett Syndrome by Modulation of Late Response Genes
通过调节晚期反应基因使 Rett 综合征中的 E:I 失衡正常化
- 批准号:
9449084 - 财政年份:2017
- 资助金额:
$ 8.23万 - 项目类别:
相似国自然基金
糖尿病ED中成纤维细胞衰老调控内皮细胞线粒体稳态失衡的机制研究
- 批准号:82371634
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
胆固醇合成蛋白CYP51介导线粒体通透性转换诱发Th17/Treg细胞稳态失衡在舍格伦综合征中的作用机制研究
- 批准号:82370976
- 批准年份:2023
- 资助金额:48.00 万元
- 项目类别:面上项目
自噬流/炎症小体失衡在新生儿缺血缺氧性脑病中的作用机制
- 批准号:82372205
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
乳杆菌代谢物PolyP通过LuxS/AI-2途径调控菌斑生物膜介导的矿化失衡机制研究
- 批准号:82370941
- 批准年份:2023
- 资助金额:48.00 万元
- 项目类别:面上项目
衰老上皮细胞FABP4调控HSDL2致脂肪酸代谢失衡在BPH发病中的机制研究
- 批准号:82370774
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
相似海外基金
The impact of effort-reward imbalance on newcomer mental health: A longitudinal investigation
努力与回报失衡对新人心理健康的影响:纵向调查
- 批准号:
24K16418 - 财政年份:2024
- 资助金额:
$ 8.23万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Imbalance between cell biomass production and envelope biosynthesis underpins the bactericidal activity of cell wall -targeting antibiotics
细胞生物量产生和包膜生物合成之间的不平衡是细胞壁靶向抗生素杀菌活性的基础
- 批准号:
2884862 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Studentship
AGS-FIRP Track 2: Understanding Vertical Variation of Energy Dissipation near the Surface for Solving the Mystery of the Observed Surface Energy Imbalance
AGS-FIRP 轨道 2:了解地表附近能量耗散的垂直变化,以解决观测到的地表能量不平衡之谜
- 批准号:
2231229 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Standard Grant
Accurate and Individualized Prediction of Excitation-Inhibition Imbalance in Alzheimer's Disease using Data-driven Neural Model
使用数据驱动的神经模型准确、个性化地预测阿尔茨海默病的兴奋抑制失衡
- 批准号:
10727356 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Genetic regulation of genes on active and inactive X chromosome and their contribution to sex-biased diseases
活性和非活性 X 染色体上基因的遗传调控及其对性别偏见疾病的贡献
- 批准号:
10751331 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance
精胺合酶缺乏和多胺失衡的神经毒性
- 批准号:
10752966 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
The intersection of diet, cell metabolic state, and SIV reservoir transcription
饮食、细胞代谢状态和 SIV 储存库转录的交叉点
- 批准号:
10618546 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Integrative analysis of whole genomes and transcriptomes from multiple cell types in rare disease patients
罕见病患者多种细胞类型的全基因组和转录组的综合分析
- 批准号:
10587683 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
The Interplay of Host Genetic Variation and the Gut Microbiome in Crohn's Disease
克罗恩病宿主遗传变异与肠道微生物组的相互作用
- 批准号:
10751276 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Non-Contact Sleep Stage Estimation: Machine Learning in Multi-Imbalance Data for Improvements in Accuracy and Interpretability
非接触式睡眠阶段估计:多重不平衡数据中的机器学习,以提高准确性和可解释性
- 批准号:
22KJ1367 - 财政年份:2023
- 资助金额:
$ 8.23万 - 项目类别:
Grant-in-Aid for JSPS Fellows