Genetic Programming in Progressive Renal Disease
Genetic Programming in Progressive Renal Disease
批准号:
8010742
负责人:
Erwin P. Bottinger
金额:
$10.68万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-01-15 至 2010-12-31
关键词:
Adaptor Signaling ProteinApoptosisBindingCD2-associated proteinCell SurvivalComplexDiabetic NephropathyDiabetic mouseDisease susceptibilityDown-RegulationDoxycyclineEpithelialEpithelial CellsGenetic ProgrammingGenotypeGrantHumanIn VitroInjuryKidneyKidney DiseasesKnockout MiceLesionLifeLigandsMediatingModelingMolecularMusMutationParietalPathway interactionsPhosphatidylinositolsPhosphotransferasesReceptor SignalingRegulationRenal glomerular diseaseRoleSignal TransductionStructural ModelsTGF-beta type I receptorTechnologyTestingTransgenesTransgenic OrganismsTubular formationUp-RegulationWorkbasediabeticglomerulosclerosisin vivomenmouse modelnovelpodocytepreventprotein complexprotein expressionprotein functionreceptorslit diaphragm
中文摘要
足细胞耗竭是进行性肾小球硬化和糖尿病肾病的标志。张- - - - - -
英文摘要
Podocyte depletion is a hallmark of progressive glomerulosclerosis and diabetic nephropathy. CD2-
associated protein (CD2AP) is a widely-expressed cytoplasmic adaptor protein that has previously been
implicated in podocyte slit diaphragm protein complex formation. CD2AP null mice develop progressive
glomerulosclerosis early in life and CD2AP haploinsufficiency is associated with glomerular disease
susceptibility in humans. However, it remains unclear how loss of CD2AP function may cause
glomerulosclerosis. In this renewal application, we will extend our work to test the hypothesis that CD2AP
promotes renal epithelial cell survival by functioning as a molecular switch that suppresses the TGF-beta
receptor type I (Tgfbr1)/Smad3-dependent apoptosis pathway and activates a Tgfbrl/phosphoinositide-3-
kinase (PI3K) -dependent survival pathway. If confirmed, our studies will provide a molecular mechanism to
explain how loss of CD2AP may enhance podocyte apoptosis and depletion to promote glomerular disease
in mice and men based on a novel, essential functional role for CD2AP as multi-pathway regulator in TbRI-
induced signal transduction. The relevance of this work is further underscored by recent observations
suggesting that in the absence of direct genetic defects, functional downregulation of CD2AP expression is a
common finding in mouse models and human glomerular disease.
Specific Aims: 1. Identify the molecular determinants and characterize the regulation of the TGF-p-inducible
interaction of CD2AP and cytoplasmic Tgfbrl. We will a) determine the sequence motif and structural model
of Tgfbrl that underlies the interaction with CD2AP, and b) compare it with the Smad-binding model
mediated by the GS region and L45 loop of Tgfbrl. 2. Investigate how CD2AP mediates negative regulation
of Tgfbr1/Smad3 signaling. We will examine whether a) CD2AP competes with SmadS for binding to
activated Tgfbrl; and b) CD2AP targets internalized Tgfbrl complexes for degradation and termination of
signaling. 3. Define the role of podocyte-specific TGF-b receptor signaling in podocyte apoptosis and
depletion in vivo, and determine whether this podocyte-specific mechanism underlies the progression of
glomerular injury to glomerulosclerosis in CD2AP-/- mice? We will determine in vivo whether a) conditional
deletion of TGF-b receptor type II (Tgfbr2) in podocytes using cre/lox technology prevents podocyte
apoptosis, depletion, and/or glomerulosclerosis in CD2AP-/- mice; and b) whether podocyte-specific,
controlled activation of TGF-(3 receptor signaling is sufficient to induce podocyte apoptosis, podocyte
depletion and glomerulosclerosis in vivo using doxycycline-inducible expression of constitutively active
Tgfbrl (Tgfbrl (AAD)).
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1161/circresaha.113.301921
发表时间:
2013-09-27
期刊:
Circulation research
影响因子:
20.1
作者:
[Xie WB, Li Z, Shi N, Guo X, Tang J, Ju W, Han J, Liu T, Bottinger EP, Chai Y, Jose PA, Chen SY]
通讯作者:
Chen SY
DOI:
10.1152/ajprenal.00559.2007
发表时间:
2008-10
期刊:
American journal of physiology. Renal physiology
影响因子:
--
作者:
[Saleem MA, Zavadil J, Bailly M, McGee K, Witherden IR, Pavenstadt H, Hsu H, Sanday J, Satchell SC, Lennon R, Ni L, Bottinger EP, Mundel P, Mathieson PW]
通讯作者:
Mathieson PW
Genomic Medicine Pilot For Hypertension And Kidney Disease In Primary Care
-
批准号:8682897
-
项目类别:
-
资助金额:$96.89万
-
财政年份:2013
-
负责人:Erwin P. Bottinger
-
依托单位:
Genomic Medicine Pilot For Hypertension And Kidney Disease In Primary Care
-
批准号:8514374
-
项目类别:
-
资助金额:$73.96万
-
财政年份:2013
-
负责人:Erwin P. Bottinger
-
依托单位:
Genomic Medicine Pilot For Hypertension And Kidney Disease In Primary Care
-
批准号:9145325
-
项目类别:
-
资助金额:$5.0万
-
财政年份:2013
-
负责人:Erwin P. Bottinger
-
依托单位:
Glomerular Cell-Cell Crosstalk and Injury
-
批准号:8506338
-
项目类别:
-
资助金额:$36.87万
-
财政年份:2013
-
负责人:Erwin P. Bottinger
-
依托单位:
Biorepository for Genomic Medicine in diverse Communities
-
批准号:8509278
-
项目类别:
-
资助金额:$27.12万
-
财政年份:2011
-
负责人:Erwin P. Bottinger
-
依托单位:
Biorepository for Genomic Medicine in diverse Communities
-
批准号:9115828
-
项目类别:
-
资助金额:$8.95万
-
财政年份:2011
-
负责人:Erwin P. Bottinger
-
依托单位:
Biorepository for Genomic Medicine in diverse Communities
-
批准号:8193636
-
项目类别:
-
资助金额:$84.75万
-
财政年份:2011
-
负责人:Erwin P. Bottinger
-
依托单位:
Biorepository for Genomic Medicine in diverse Communities
-
批准号:8729076
-
项目类别:
-
资助金额:$18.05万
-
财政年份:2011
-
负责人:Erwin P. Bottinger
-
依托单位:
Biorepository for Genomic Medicine in diverse Communities
-
批准号:8537968
-
项目类别:
-
资助金额:$104.26万
-
财政年份:2011
-
负责人:Erwin P. Bottinger
-
依托单位:
Biorepository for Genomic Medicine in diverse Communities
-
批准号:8319368
-
项目类别:
-
资助金额:$82.54万
-
财政年份:2011
-
负责人:Erwin P. Bottinger
-
依托单位:
The New York CKD Biomarker Discovery Program
-
批准号:7800090
-
项目类别:
-
资助金额:$60.58万
-
财政年份:2009
-
负责人:Erwin P. Bottinger
-
依托单位:
The New York CKD Biomarker Discovery Program
-
批准号:8312652
-
项目类别:
-
资助金额:$58.88万
-
财政年份:2009
-
负责人:Erwin P. Bottinger
-
依托单位:
The New York CKD Biomarker Discovery Program
-
批准号:7938633
-
项目类别:
-
资助金额:$58.88万
-
财政年份:2009
-
负责人:Erwin P. Bottinger
-
依托单位:
The New York CKD Biomarker Discovery Program
-
批准号:8537432
-
项目类别:
-
资助金额:$58.73万
-
财政年份:2009
-
负责人:Erwin P. Bottinger
-
依托单位:
Role and Mechanisms of Epithelial Injury in Diabetic Nephropathy
-
批准号:7896030
-
项目类别:
-
资助金额:$10.37万
-
财政年份:2009
-
负责人:Erwin P. Bottinger
-
依托单位:
The New York CKD Biomarker Discovery Program
-
批准号:8113928
-
项目类别:
-
资助金额:$58.88万
-
财政年份:2009
-
负责人:Erwin P. Bottinger
-
依托单位:
Towards Molecular Diagnostics of Glomerular Disease
-
批准号:7578177
-
项目类别:
-
资助金额:$30.35万
-
财政年份:2006
-
负责人:Erwin P. Bottinger
-
依托单位:
Towards Molecular Diagnostics of Glomerular Disease
-
批准号:7217515
-
项目类别:
-
资助金额:$30.97万
-
财政年份:2006
-
负责人:Erwin P. Bottinger
-
依托单位:
Towards Molecular Diagnostics of Glomerular Disease
-
批准号:7028518
-
项目类别:
-
资助金额:$33.32万
-
财政年份:2006
-
负责人:Erwin P. Bottinger
-
依托单位:
Towards Molecular Diagnostics of Glomerular Disease
-
批准号:7379955
-
项目类别:
-
资助金额:$30.35万
-
财政年份:2006
-
负责人:Erwin P. Bottinger
-
依托单位:
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