Molecular mechanisms of podocyte injury in FSGS
FSGS足细胞损伤的分子机制
基本信息
- 批准号:10264943
- 负责人:
- 金额:$ 41.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-03-10 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAntioxidantsApplications GrantsBRAF geneCell DeathCell membraneCellsCessation of lifeChronic Kidney FailureClinicCoenzyme Q10DataDevelopmentEnzymesEventFDA approvedFocal Segmental GlomerulosclerosisFundingGene ExpressionGenerationsGeneticGoalsGrantHumanIn VitroInjuryInsertional ActivationsIon ChannelKidneyKidney DiseasesKidney FailureLeadLipidsMAP Kinase GeneMediatingMitochondriaMitoticModelingMolecularMusMutationNephrotic SyndromePathway interactionsPatientsPharmaceutical PreparationsPrevalenceProteinuriaPublishingReceptor SignalingReceptor, Angiotensin, Type 1Retinoic Acid ReceptorSignal PathwaySignal TransductionStressTestingTherapeuticTissuesUp-RegulationWorkbasedisease-causing mutationendoplasmic reticulum stressin vivoinnovationinsightlipid metabolismloss of functionmetabolomicsnew therapeutic targetnovelnovel therapeuticspodocytepreventsmall moleculestressortargeted treatmenttranscriptomics
项目摘要
SUMMARY
Chronic kidney diseases affect more than 700 million people worldwide, and are a frequent cause
of kidney failure and death. A key event leading to kidney failure is filter damage, caused by the
loss of podocytes. This is a cause of a kidney disease known as Focal segmental
Glomerulosclerosis (FSGS). Despite the growing prevalence of kidney diseases, there are
currently no FDA approved therapies to prevent the loss of podocytes. The goal of this grant
application is to gain a deep understanding of the molecular mechanisms involved in podocyte
injury related to the BRAF signaling pathway, so that it may be targeted for therapeutic benefit.
We started with a rare genetic kidney disease caused by mutations in an enzyme called PDSS2.
Interestingly, we found that the loss of function of this enzyme causes podocytes to die, resulting
in FSGS. We subsequently found that a key molecule in preventing podocyte death is BRAF and
a small molecule that activates BRAF, called GDC-0879, can protect podocytes from cell death.
In fact, GDC-0879 was able to protect podocytes from several injuries including toxic lipids and
other stress-causing molecules. Most excitingly, we now have evidence that GDC-0879 protects
mice from podocyte injury and the resulting kidney filter damage (called proteinuria). Here, we will
explore the precise molecular mechanisms involved in BRAF-related podocyte injury, and the
potential for GDC-0879 to become a treatment for FSGS.
Successful completion of this work may provide a new, much needed treatment for FSGS and
chronic kidney diseases, and one that may be easily brought to the clinic, since GDC-0879 is
already an FDA approved drug for other indications.
概括
慢性肾脏病影响着全世界 7 亿多人,并且是常见的原因
肾衰竭和死亡。导致肾衰竭的一个关键事件是过滤器损坏,这是由
足细胞丢失。这是一种称为局灶节段性肾脏疾病的原因
肾小球硬化症(FSGS)。尽管肾脏疾病的患病率不断上升,但
目前尚无 FDA 批准的疗法来防止足细胞丢失。本次赠款的目标
应用是为了深入了解足细胞涉及的分子机制
损伤与 BRAF 信号通路相关,因此可以作为治疗益处的目标。
我们从一种罕见的遗传性肾病开始,这种疾病是由一种名为 PDSS2 的酶突变引起的。
有趣的是,我们发现这种酶功能的丧失会导致足细胞死亡,从而导致
在 FSGS 中。我们随后发现防止足细胞死亡的关键分子是 BRAF 和
一种激活 BRAF 的小分子,称为 GDC-0879,可以保护足细胞免于细胞死亡。
事实上,GDC-0879 能够保护足细胞免受多种损伤,包括有毒脂质和
其他引起压力的分子。最令人兴奋的是,我们现在有证据表明 GDC-0879 可以保护
小鼠免受足细胞损伤以及由此导致的肾过滤器损伤(称为蛋白尿)。在这里,我们将
探讨 BRAF 相关足细胞损伤的精确分子机制,以及
GDC-0879 成为 FSGS 治疗方法的潜力。
这项工作的成功完成可能会为 FSGS 和 FSGS 提供急需的新治疗方法。
慢性肾脏疾病,并且是一种很容易带到诊所的疾病,因为 GDC-0879 是
已获得 FDA 批准用于其他适应症的药物。
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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Anna Greka其他文献
Anna Greka的其他文献
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{{ truncateString('Anna Greka', 18)}}的其他基金
Role of TRPC5 channel inhibition in the treatment of glomerular disease
TRPC5通道抑制在肾小球疾病治疗中的作用
- 批准号:
8760609 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Ion-channel targeted therapy for progressive kidney diseases
进行性肾脏疾病的离子通道靶向治疗
- 批准号:
10453797 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Role of TRPC5 channel inhibition in the treatment of glomerular disease
TRPC5通道抑制在肾小球疾病治疗中的作用
- 批准号:
8927620 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Ion-channel targeted therapy for progressive kidney diseases
进行性肾脏疾病的离子通道靶向治疗
- 批准号:
10216240 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Molecular mechanisms of podocyte injury in FSGS
FSGS足细胞损伤的分子机制
- 批准号:
10408161 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Molecular mechanisms of podocyte injury in FSGS
FSGS足细胞损伤的分子机制
- 批准号:
10120140 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Molecular mechanisms of AT1R signaling in FSGS
FSGS 中 AT1R 信号传导的分子机制
- 批准号:
8868258 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
Role of TRPC5 channel inhibition in the treatment of glomerular disease
TRPC5通道抑制在肾小球疾病治疗中的作用
- 批准号:
9121550 - 财政年份:2014
- 资助金额:
$ 41.26万 - 项目类别:
TRPC-mediated calcium signaling in podocytes
足细胞中 TRPC 介导的钙信号传导
- 批准号:
8542130 - 财政年份:2012
- 资助金额:
$ 41.26万 - 项目类别:
TRPC channels in proteinuric kidney disease
TRPC 通道在蛋白尿肾病中的作用
- 批准号:
8063458 - 财政年份:2010
- 资助金额:
$ 41.26万 - 项目类别:
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