Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
基本信息
- 批准号:8065715
- 负责人:
- 金额:$ 7.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-05-01 至 2012-09-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAgonistAllelesAngiotensin IIAnimal ModelAnimalsAnkyrin RepeatApoptosisCalciumCalcium SignalingCationsCell LineCell physiologyCellsCytoskeletal ProteinsDataDevelopmentDiseaseEnd stage renal failureEtiologyFamilyFocal Segmental GlomerulosclerosisFunctional disorderGenesGlutamineHereditary DiseaseHumanHuman Cell LineIn VitroIndiumIndividualInjuryInjury to KidneyKidneyKidney DiseasesKnock-in MouseLigandsMaintenanceMediatingModelingMusMutationNew ZealandPathogenesisPathologyPathway interactionsPatientsPermeabilityPhenotypePlayPoint MutationPositioning AttributePrevalenceProlineProteinsProteinuriaResearch PersonnelResistanceResourcesRoleSeriesSignal TransductionStructureTestingTissuesTransgenic MiceWorkcell growthdisease phenotypedisease-causing mutationembryonic stem cellgain of functionglomerular functionhomologous recombinationin vivokindredmouse modelmutantnephrogenesispodocyteprogramsreceptorrelease of sequestered calcium ion into cytoplasmresponsetrafficking
项目摘要
DESCRIPTION (provided by applicant): We have previously identified a point mutation in thes Transient Receptor Potential Cation Channel 6 (TRPC6) gene causing an autosomal dominant form of familial focal and segmental glomerulosclerosis (FSGS). This P112Q substitution causes a marked alteration in TRPC6-mediated calcium signals in response to agonists such as angiotensin II. However, the precise mechanism by which the TRPC6P112Q mutation leads to the prototypical disease phenotype of FSGS is not clear. We hypothesize that the presence of a single TRPC6P112Q allele causes an intermediate phenotype which is sufficient to promote the development of renal disease and that the TRPC6P112Q protein may amplify injurious signals triggered by ligands such as angiotensin II that play a key role in promoting kidney injury and proteinuria. To test these hypotheses, we propose the following specific aims: (1) To define the intermediate phenotype conferred by heterozygosity for the TRPC6P112Q mutation in a unique resource of human cell lines from the FSGS2 family. These cell lines will be used to define the consequences of this mutation on calcium signaling, TRPC6 trafficking, cell growth and apoptosis. (2) To establish causality of the TRPC6P112Q mutation for FSGS using a mouse model. Extending the in vitro work in specific aim 1 to the in vivo setting, we will develop a knock-in mouse model of the heterozygous TRPC6P112Q mutation. (3) To determine whether expression of the TRPC6P112Q mutation only in podocytes is sufficient to cause proteinuria. TRPC6 is expressed in podocytes and abnormalities of podocyte function are essential to the pathogenesis of FSGS. We suggest that expression of the TRPC6P112Q protein in podocytes disrupts key cellular functions and we will test this by generating a transgenic mouse line expressing the mutant TRPC6P112Q protein only in podocytes. We anticipate that these animals will develop overt proteinuria and FSGS. (4) To define the consequences of TRPC6 deficiency in the kidney. We have hypothesized that the TRPC6P112Q mutation causes a gain-of-function phenotype of exaggerated calcium flux that generates glomerular injury. It is possible that the mutation alters some critical function of TRPC6 necessary for maintaining normal glomerular function. To distinguish these possibilities, kidney structure and function will be examined in a line of -/-TRPC6 mice. Our original hypothesis suggests that the absence of TRPC6 may confer resistance to kidney injury and proteinuria. We will test this in models of induced renal disease.
描述(由申请人提供):我们先前已经鉴定了瞬时受体电位阳离子通道6(TRPC 6)基因中的一个点突变,该点突变导致常染色体显性形式的家族性局灶性节段性肾小球硬化症(FSGS)。这种P112 Q取代引起TRPC 6介导的钙信号响应于激动剂如血管紧张素II的显著改变。然而,TRPC 6P 112 Q突变导致FSGS原型疾病表型的确切机制尚不清楚。我们假设,一个单一的TRPC 6P 112 Q等位基因的存在导致一个中间表型,这是足以促进肾脏疾病的发展,TRPC 6P 112 Q蛋白可能会放大由配体,如血管紧张素II,在促进肾损伤和蛋白尿发挥关键作用触发的有害信号。为了验证这些假设,我们提出了以下具体目标:(1)在来自FSGS 2家族的独特人类细胞系资源中定义TRPC 6P 112 Q突变的杂合性所赋予的中间表型。这些细胞系将用于确定这种突变对钙信号传导、TRPC 6运输、细胞生长和凋亡的影响。(2)使用小鼠模型确定TRPC 6P 112 Q突变与FSGS的因果关系。将特定目标1中的体外工作扩展到体内环境,我们将开发杂合TRPC 6P 112 Q突变的敲入小鼠模型。(3)确定TRPC 6P 112 Q突变仅在足细胞中表达是否足以引起蛋白尿。TRPC 6在足细胞中表达,足细胞功能异常在FSGS的发病机制中至关重要。我们认为TRPC 6P 112 Q蛋白在足细胞中的表达破坏了关键的细胞功能,我们将通过产生仅在足细胞中表达突变TRPC 6P 112 Q蛋白的转基因小鼠系来测试这一点。我们预计这些动物将出现明显的蛋白尿和FSGS。(4)明确肾脏TRPC 6缺乏的后果。我们假设TRPC 6P 112 Q突变导致功能获得性表型的钙流量增加,从而导致肾小球损伤。这是可能的,突变改变了一些关键功能的TRPC 6维持正常肾小球功能所必需的。为了区分这些可能性,将在一系列-/-TRPC 6小鼠中检查肾脏结构和功能。我们最初的假设表明,TRPC 6的缺乏可能赋予抵抗肾损伤和蛋白尿。我们将在诱发性肾病模型中对此进行测试。
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 }}
MICHELLE P. WINN其他文献
MICHELLE P. WINN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('MICHELLE P. WINN', 18)}}的其他基金
Gene Discovery in Autosomal Dominant Focal Segmental Glomerulosclerosis
常染色体显性局灶节段性肾小球硬化症的基因发现
- 批准号:
8438310 - 财政年份:2012
- 资助金额:
$ 7.28万 - 项目类别:
Gene Discovery in Autosomal Dominant Focal Segmental Glomerulosclerosis
常染色体显性局灶节段性肾小球硬化症的基因发现
- 批准号:
8547065 - 财政年份:2012
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
7869494 - 财政年份:2009
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
7921104 - 财政年份:2009
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
8287198 - 财政年份:2006
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
7610984 - 财政年份:2006
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
7224907 - 财政年份:2006
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
7417914 - 财政年份:2006
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
7084165 - 财政年份:2006
- 资助金额:
$ 7.28万 - 项目类别:
Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis
TRPC6 作为局灶性和节段性肾小球硬化病因的特征
- 批准号:
8069364 - 财政年份:2006
- 资助金额:
$ 7.28万 - 项目类别:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 7.28万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 7.28万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
- 批准号:
23K05057 - 财政年份:2023
- 资助金额:
$ 7.28万 - 项目类别:
Grant-in-Aid for Scientific Research (C)