Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS.
描述单基因 SRNS/FSGS 中 NOS1AP 和 TRIM8 突变的致病机制。
基本信息
- 批准号:10214843
- 负责人:
- 金额:$ 16.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAdaptor Signaling ProteinAdvisory CommitteesAlbuminuriaAntibodiesBiologicalBloodBostonCDC42 geneCell physiologyCellsChildChildhoodChronicChronic Kidney FailureCo-ImmunoprecipitationsCoupledCreatinineCritical PathwaysDataDefectDevelopment PlansDiffuseDiseaseDisease modelEdemaElectron MicroscopyEnd stage renal failureEnsureEnvironmentEpilepsyExhibitsFamilyFocal Segmental GlomerulosclerosisFoot ProcessFunctional disorderFundingGenesGeneticGrantGrowthGuanine Nucleotide Exchange FactorsHandHumanHypoalbuminemiaImmunofluorescence ImmunologicImmunoprecipitationImpairmentKidneyKidney FailureKidney GlomerulusKnock-inLabelLaboratoriesLifeMediatingMedicineMentorsMethodologyMicroscopyModelingMusMutateMutationNephrologyNephrotic SyndromeNitric Oxide Synthase Type INuclearNucleoplasmPathogenesisPathogenicityPathway interactionsPatientsPediatric HospitalsProgram DevelopmentProteinsProteinuriaProteomicsPublicationsResearchResearch ProposalsResearch SupportResistanceRoleScienceSerumSerum AlbuminServicesSteroid therapySteroid-resistant idiopathic nephrotic syndromeStructureTrainingUbiquitinUrineVocational GuidanceWestern Blottingbasecareercareer developmentglomerulosclerosisinnovationkidney biopsylight microscopyliquid chromatography mass spectrometrymedical schoolsmeetingsmigrationmouse modelmutantnoveloverexpressionpodocyteresearch and developmentsuccesssymposiumubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Title:Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS
Steroid resistant nephrotic syndrome (SRNS) is a leading cause of childhood chronic kidney disease1, marked
by proteinuria and edema. Renal biopsy typically reveals focal segmental glomerulosclerosis (FSGS). 59% of
children with SRNS are unresponsive to standard therapy1,2. A majority of them progress to end-stage renal
disease with loss of the kidney glomerular filtering cells, podocytes1,2. Mendelian genetic causes of SRNS/FSGS
have been detected in ~11-30% of pediatric cases3–6. SRNS/FSGS disease genes encode critical pathway
components in podocyte biology2,7–10. Human mutations impair these SRNS/FSGS pathways, causing
podocytopathies2,7–10.
The proposed research will explore the pathogenic mechanisms underlying two novel monogenic causes of
SRNS/FSGS in human NOS1AP and TRIM8 mutations, which were discovered by the applicant. The applicant’s
preliminary data generated the hypothesis that human NOS1AP and TRIM8 mutations cause SRNS/FSGS
through dysregulation of the CDC42 pathway and TRIM8 E3 ligase functions, respectively. The applicant,
thus, proposes the following specific aims (SAs) using innovative cell biological, proteomics, and mouse
models approaches: (SA1) Define the mechanism of CDC42 dysregulation caused by NOS1AP SRNS
mutations; (SA2) Dissect the pathogenesis of TRIM8 SRNS/FSGS mutations in podocytes; (SA3) Delineate the
pathogenesis of NOS1AP and TRIM8 mutations in SRNS in mice.
The applicant has created a comprehensive career development plan supported by his mentor to (1)
ensure his progress and success in carrying out this research proposal and (2) to facilitate his transition
to an independent research career focused on disease modeling of nephrotic syndrome. This plan begins
with regular meetings with his mentor and advisory committee—national and global academic leaders in
medicine and science—to provide research and career guidance. The plan additionally includes (i) research and
career development seminars, (ii) proteomics and microscopy methodology courses and (iii) activities for career
growth including conference presentations and publications, mentoring of junior trainees, and application for
independent research funding. The applicant and mentor have, also, agreed upon a transition plan to distinguish
himself from the mentor’s laboratory. His training will be carried out in an unparalleled academic environment at
Boston Children’s Hospital and Harvard Medical School, which provides dedicated career development
programs and all necessary research support and supplies through his mentor and institutional core services.
Collectively, this research and career development proposal is a product of the applicant’s ambition and
capacity to transition to an independent research career in nephrology.
项目摘要
标题:描述单基因SRNS/FSGS中NOS 1AP和TRIM 8突变的致病机制
激素抵抗性肾病综合征(SRNS)是儿童慢性肾病的主要原因1,
蛋白尿和水肿肾活检通常显示局灶节段性肾小球硬化症(FSGS)。59%的
SRNS患儿对标准治疗无反应1,2.其中大多数进展到终末期肾
肾小球滤过细胞(足细胞)丧失的疾病1,2。SRNS/FSGS的孟德尔遗传原因
在约11-30%的儿科病例中检测到3 -6。SRNS/FSGS疾病基因编码关键途径
成分在足细胞生物学2,7-10。人类突变会损害这些SRNS/FSGS途径,
podocytopathies2,7-10.
这项研究将探索两种新的单基因病因的致病机制,
人NOS 1AP和TRIM 8突变中的SRNS/FSGS,其由申请人发现。申请人的
初步数据产生了一个假设,即人类NOS 1AP和TRIM 8突变导致SRNS/FSGS
分别通过CDC 42通路和TRIM 8 E3连接酶功能的失调。申请人,
因此,提出了以下具体目标(SA),使用创新的细胞生物学,蛋白质组学和小鼠
模型方法:(SA 1)确定NOS 1AP SRNS引起的CDC 42失调的机制
(SA 2)剖析足细胞中TRIM 8 SRNS/FSGS突变的发病机制;(SA 3)描述足细胞中TRIM 8 SRNS/FSGS突变的发病机制;(SA 4)描述足细胞中TRIM 8 SRNS/FSGS突变的发病机制;(SA 5)描述足细胞中TRIM 8 SRNS/FSGS突变的发病机制。
小鼠SRNS中NOS 1AP和TRIM 8突变的发病机制。
申请人已经制定了一个全面的职业发展计划,并得到了导师的支持,以(1)
确保他在实施这项研究计划方面取得进展和成功,以及(2)促进他的过渡
到一个独立的研究生涯,专注于肾病综合征的疾病建模。这个计划开始于
定期与他的导师和咨询委员会-国家和全球学术领袖,
医学和科学-提供研究和职业指导。该计划还包括(一)研究和
职业发展研讨会,(ii)蛋白质组学和显微镜方法学课程和(iii)职业活动
增长,包括会议演讲和出版物,初级学员的辅导,以及申请
独立研究经费。申请人和导师还商定了一个过渡计划,
从导师的实验室里他的培训将在无与伦比的学术环境中进行,
波士顿儿童医院和哈佛医学院,提供专门的职业发展
计划和所有必要的研究支持和用品通过他的导师和机构的核心服务。
总的来说,这个研究和职业发展计划是申请人的雄心壮志的产物,
有能力过渡到肾脏病学的独立研究生涯。
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)
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Amar J Majmundar其他文献
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{{ truncateString('Amar J Majmundar', 18)}}的其他基金
Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS.
描述单基因 SRNS/FSGS 中 NOS1AP 和 TRIM8 突变的致病机制。
- 批准号:
10596564 - 财政年份:2021
- 资助金额:
$ 16.94万 - 项目类别:
Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS.
描述单基因 SRNS/FSGS 中 NOS1AP 和 TRIM8 突变的致病机制。
- 批准号:
10379338 - 财政年份:2021
- 资助金额:
$ 16.94万 - 项目类别: