Mouse models of Pik3ca brain overgrowth disorders
Pik3ca 大脑过度生长障碍的小鼠模型
基本信息
- 批准号:9905565
- 负责人:
- 金额:$ 60.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AKT Signaling PathwayAcuteAdultAllelesAntiepileptic AgentsAntineoplastic AgentsApoptosisAutomobile DrivingBiological AssayBiological ModelsBlood capillariesBrainBrain DiseasesBrain PathologyCLOVES syndromeCell SizeCell divisionChildChimera organismCortical DysplasiaCortical MalformationDataDefectDevelopmentDiffuse DysplasiaDiseaseDysplasiaElectroporationEmbryoEnzymesEpidermal nevusEpilepsyExcisionExhibitsFRAP1 geneGene MutationGerm-Line MutationHandHippocampus (Brain)Hot SpotHourHumanIndividualIntellectual functioning disabilityIntractable EpilepsyLeadMalignant NeoplasmsMegalencephalyModelingMolecularMosaicismMusMutant Strains MiceMutationNeuronsOperative Surgical ProceduresPIK3CA genePathogenesisPathway interactionsPatientsPharmacologyPharmacotherapyPhenotypePhosphatidylinositolsPhosphotransferasesProteomicsProto-Oncogene Proteins c-aktReportingReproducibilityResistanceRoleSeborrheic keratosisSeizuresSeriesSeveritiesSideSignal PathwaySignal TransductionSirolimusStructural defectSyndromeTechnologyTestingautism spectrum disorderbaseblastocystbrain overgrowthcancer typechildhood epilepsyclinically relevantcritical developmental perioddevelopmental diseaseembryonic stem cellexperimental studygain of functiongain of function mutationgenetic approachhemimegalencephalyhuman modelin uteroinhibitor/antagonistmTOR Inhibitormalformationmigrationmouse modelmutantnerve stem cellnovel therapeuticspre-clinicalstandard of carestem cells
项目摘要
PROJECT SUMMARY
This proposal outlines a comprehensive series of experiments to assess the basis of overgrowth phenotypes
associated with gain of function mutations in PIK3CA, using the mouse as a model system. Although well
studied in cancer, recent data has revealed a role for PIK3CA mutation in several developmental disorders
including MCAP, DMEG, CLOVES syndrome, epidermal nevi and seborrheic keratosis. Here will assess the
developmental and signaling pathway disruptions caused by 3 different Pik3ca gain of function mutations, with
particular emphasis on the developing brain. To date, all reported PIK3CA mutations are postzygotic or mosaic
rather than germline mutations. Accordingly, we hypothesize that PIK3CA phenotypes correlate with both the
severity of the mutation and level (and distribution) of mosaicism. To test this and other hypotheses, we will
use standard conditional genetic approaches to express 3 patient-related Pik3ca gof mutations in embryonic
CNS neuronal progenitors and their descendants. We will then generate ES cell chimeras, injecting ES cells
constitutively expressing the same mutations into wild-type blastocysts to assess phenotype-mosaicism
relationships both within the brain and throughout the entire body. We also propose to use in utero
electroporation technology to more specifically target mosaic expression to the developing brain. Our studies
will assess the developmental pathogenesis of brain pathology and characterize the associated epilepsy, a
pressing clinically relevant phenotype. Finally, we will use pharmacological approaches to assess the
underlying mechanisms driving acutely Pik3ca-dependent seizures in post-natal mice. These assays represent
the first step toward developing molecularly rational epilepsy therapy in PIK3CA segmental brain overgrowth
syndrome patients.
项目总结
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 }}
Kathleen Joyce Millen其他文献
Kathleen Joyce Millen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('Kathleen Joyce Millen', 18)}}的其他基金
Building transgenic tools in Acomys cahirinus, an emerging model for mammalian regenerative biology and healthy aging
在 Acomys cahirinus 中构建转基因工具,这是一种哺乳动物再生生物学和健康衰老的新兴模型
- 批准号:
10327728 - 财政年份:2021
- 资助金额:
$ 60.5万 - 项目类别:
Pathological Mechanisms of Human Cerebeller Malformations
人类小脑畸形的病理机制
- 批准号:
10076489 - 财政年份:2020
- 资助金额:
$ 60.5万 - 项目类别:
Mouse models of Pik3ca brain overgrowth disorders
Pik3ca 大脑过度生长障碍的小鼠模型
- 批准号:
9331300 - 财政年份:2017
- 资助金额:
$ 60.5万 - 项目类别:
New transgenic tools for mammalian fibrosis and regenerative repair research
用于哺乳动物纤维化和再生修复研究的新转基因工具
- 批准号:
9331056 - 财政年份:2017
- 资助金额:
$ 60.5万 - 项目类别:
Pathological Mechanisms of Human Cerebellar Malformations
人类小脑畸形的病理机制
- 批准号:
10456683 - 财政年份:2016
- 资助金额:
$ 60.5万 - 项目类别:
Pathological Mechanisms of Human Cerebellar Malformations
人类小脑畸形的病理机制
- 批准号:
10467630 - 财政年份:2016
- 资助金额:
$ 60.5万 - 项目类别:
Pathological Mechanisms of Human Cerebellar Malformations
人类小脑畸形的病理机制
- 批准号:
10672203 - 财政年份:2016
- 资助金额:
$ 60.5万 - 项目类别:
Megalencephaly and segmental brain overgrowth in humans
人类巨脑畸形和节段性大脑过度生长
- 批准号:
9751409 - 财政年份:2015
- 资助金额:
$ 60.5万 - 项目类别:
Congenital brain malformations caused by aberrant head mesenchymal signaling
头部间质信号异常引起的先天性脑畸形
- 批准号:
8539859 - 财政年份:2012
- 资助金额:
$ 60.5万 - 项目类别:
Congenital brain malformations caused by aberrant head mesenchymal signaling
头部间质信号异常引起的先天性脑畸形
- 批准号:
9086446 - 财政年份:2012
- 资助金额:
$ 60.5万 - 项目类别:
相似海外基金
Un/kindness, shame & resistance: the care of inpatients in NHS adult acute mental health units and how it might be improved
Un/善良,羞耻
- 批准号:
2885806 - 财政年份:2023
- 资助金额:
$ 60.5万 - 项目类别:
Studentship
Post-Acute Care Transitions for Older Adult Medicare Beneficiaries with Serious Mental Illness
患有严重精神疾病的老年医疗保险受益人的急性后护理过渡
- 批准号:
10772386 - 财政年份:2023
- 资助金额:
$ 60.5万 - 项目类别:
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
474619 - 财政年份:2022
- 资助金额:
$ 60.5万 - 项目类别:
Operating Grants
Investigating the impact acute inhalation of cannabis with a high content of delta-9-tetrahydrocannabinol has on myelination and microglia in adult and aged mice
研究急性吸入高含量 delta-9-四氢大麻酚的大麻对成年和老年小鼠髓鞘形成和小胶质细胞的影响
- 批准号:
485965 - 财政年份:2022
- 资助金额:
$ 60.5万 - 项目类别:
Studentship Programs
Paving The Way to a Canadian Standard of Care with CAR-T Cellular Therapy: Phase II Trial of CD19 CAR-T for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia (CLIC-01A)
通过 CAR-T 细胞疗法为加拿大护理标准铺平道路:CD19 CAR-T 治疗复发/难治性成人急性淋巴细胞白血病的 II 期试验 (CLIC-01A)
- 批准号:
466358 - 财政年份:2022
- 资助金额:
$ 60.5万 - 项目类别:
Operating Grants
Metabolomics for prediction of cisplatin mediated acute kidney injury: a Canadian multi-centre adult and pediatric study
预测顺铂介导的急性肾损伤的代谢组学:加拿大多中心成人和儿童研究
- 批准号:
402040 - 财政年份:2019
- 资助金额:
$ 60.5万 - 项目类别:
Operating Grants
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 60.5万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Causal effect of time-varying driving pressures on mortality in mechanically ventilated, adult patients with acute respiratory distress syndrome
时变驱动压力对机械通气成年急性呼吸窘迫综合征患者死亡率的因果影响
- 批准号:
377313 - 财政年份:2017
- 资助金额:
$ 60.5万 - 项目类别:
Studentship Programs
Role of SETBP1 in adult Ph+ acute lymphoblastic leukemia
SETBP1 在成人 Ph 急性淋巴细胞白血病中的作用
- 批准号:
9315111 - 财政年份:2016
- 资助金额:
$ 60.5万 - 项目类别:
Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
成体颗粒细胞的急性抑制及其抗抑郁作用
- 批准号:
8734273 - 财政年份:2013
- 资助金额:
$ 60.5万 - 项目类别: