Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
基本信息
- 批准号:10462701
- 负责人:
- 金额:$ 50.82万
- 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:2021-09-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAnimal ModelAutosomal Dominant Polycystic KidneyBindingBiological AssayClinical TrialsCollaborationsCombined Modality TherapyCouplesCyclic GMPCystDataDoxycyclineDrug TargetingEnd stage renal failureEpithelial cystExtracellular MatrixFibrosisFocal Adhesion Kinase 1FundingGenesGeneticGenetic TranscriptionGoalsGrantGrowthHumanKidneyKidney DiseasesLipidsMass Spectrum AnalysisMediatingMedicineMessenger RNAMusMutationPTK2 genePathogenesisPatientsPersonsPharmaceutical PreparationsPharmacologyPhosphotransferasesPlayProprotein Convertase 1Proprotein Convertase 2ProteinsRenal functionRoleSignal PathwaySignal TransductionTechniquesTechnologyTestingTherapeuticTimeToxic effectTranslatingUniversitiesbasediscoidin domain receptor 1drug candidategenetic approachhuman diseasein vivoinhibitorinsightinterestinterstitialkinase inhibitormouse modelnew therapeutic targetnovelnovel strategiespolycystic kidney disease 1 proteinpreservationtandem mass spectrometrytherapeutic targettolvaptan
项目摘要
Autosomal-dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide and is
a common cause of end-stage kidney disease (ESKD). ADPKD is caused by mutations in one of two genes,
PKD1 or PKD2, which encodes polycystin 1 (PC) and PC2 respectively. Loss of PC1 or PC2 results in
activation of numerous kinases and downstream signaling pathways, which is central to the pathogenesis of
cyst growth in ADPKD. In addition, pharmacologically inhibiting a number of different kinases up-regulated in
PKD kidneys has been shown to slow cyst growth in animal models of PKD making kinase inhibitors among
the most promising class of drug candidates to treat patients with ADPKD. However, while the human kinome
consists of more than 500 kinases, only a fraction of these kinases have been tested to determine if they play a
role in ADPKD pathogenesis. As a result, there are likely many kinases that are active in ADPKD kidneys that
play prominent roles in cyst growth that are yet-to-be discovered and may be good therapeutic targets.
In collaboration with James Duncan at Temple University, we have now adapted a novel approach to
broadly screen PKD kidneys in an unbiased manner for kinases that are more active in lysates from
PKD kidneys compared with lysates from wild type kidneys. In this assay, active kinases are affinity
captured by passing lysates over multiplex inhibitor beads (MIB) containing a cocktail of kinase inhibitors.
Bound kinases are then identified by LC separation followed by quantitative tandem mass spectrometry (LC-
MS/MS). Using this approach, we have now identified a number of both known and unknown kinases
specifically up-regulated and down-regulated in PKD kidneys.
The major goal of this proposal is to assess the role of several of the kinases identified thus far whose activity
is increased in PKD kidneys and determine whether inhibiting or activating any of the kinases identified slows
cyst growth, inhibits interstitial fibrosis, and preserves renal function in animal models of ADPKD. We will then
take both biased and unbiased approaches to identify the signaling pathways regulated by these kinases that
are critical to pathogenesis with the goal of developing a more complete picture of the relevant signaling hubs
and networks that are aberrantly activated in PKD kidneys. In addition, we will use this technology to broadly
screen PKD kidneys from a variety of different “early” and “late” mouse models of ADPKD at different stages in
cyst formation and in kidneys from human patients with ADPKD to identify in an unbiased manner additional
kinases that are activated and inhibited in PKD kidneys to determine the similarities and differences between
mouse models, which kinases may be most relevant to human disease, and whether distinct sets of kinases
are activated early post cyst induction and function as early “drivers” of cyst growth. Ultimately, we hope this
new information will identify new safe drug targets and rational approaches to combination therapies to slow
cyst growth that can then be translated into clinical trials.
常染色体显性多囊肾病(ADPKD)影响全球超过1200万人,
终末期肾病(ESKD)的常见原因。ADPKD是由两个基因之一的突变引起的,
PKD 1或PKD 2,分别编码多囊蛋白1(PC)和PC 2。PC 1或PC 2丢失导致
许多激酶和下游信号通路的激活,这是发病机制的核心。
ADPKD囊肿生长。此外,抑制一些不同的激酶上调,
在PKD动物模型中,PKD肾脏已显示出减缓囊肿生长,
最有希望的一类候选药物治疗ADPKD患者。然而,尽管人类激酶组
由超过500种激酶组成,只有一小部分这些激酶已经过测试,以确定它们是否发挥作用。
在ADPKD发病机制中的作用。因此,ADPKD肾脏中可能有许多活跃的激酶,
在囊肿生长中起着重要作用,这些作用尚未被发现,可能是良好的治疗靶点。
与坦普尔大学的詹姆斯邓肯合作,我们现在已经采用了一种新的方法,
以无偏的方式广泛筛选PKD肾脏中在来自
PKD肾与来自野生型肾的裂解物的比较。在该测定中,活性激酶是亲和的。
通过使裂解物通过含有激酶抑制剂混合物的多重抑制剂珠(MIB)来捕获。
然后通过LC分离,随后通过定量串联质谱法(LC-MS)鉴定结合的激酶。
MS/MS)。使用这种方法,我们现在已经确定了一些已知和未知的激酶
尤其是在PKD肾脏中上调和下调。
这项建议的主要目标是评估迄今为止确定的几种激酶的作用,这些激酶的活性
在PKD肾脏中增加,并确定是否抑制或激活任何鉴定的激酶,
囊肿生长,抑制间质纤维化,并保护ADPKD动物模型的肾功能。然后我们将
采取有偏见和无偏见的方法来确定由这些激酶调节的信号通路,
对发病机理至关重要,目的是更全面地了解相关信号中枢
以及PKD肾脏中异常激活的网络。此外,我们将利用这项技术广泛地
在不同阶段从各种不同的ADPKD“早期”和“晚期”小鼠模型中筛选PKD肾脏,
囊肿形成和ADPKD人类患者肾脏中,以公正的方式确定其他
在PKD肾脏中激活和抑制的激酶,以确定
小鼠模型,哪些激酶可能与人类疾病最相关,以及不同的激酶组是否
在囊肿诱导后早期被激活,并作为囊肿生长的早期“驱动器”发挥作用。最终,我们希望
新的信息将确定新的安全药物靶点和合理的联合治疗方法,以减缓
囊肿生长,然后可以转化为临床试验。
项目成果
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{{ truncateString('EDWARD Y SKOLNIK', 18)}}的其他基金
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
- 批准号:
10629396 - 财政年份:2021
- 资助金额:
$ 50.82万 - 项目类别:
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
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10395477 - 财政年份:2019
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Histidine Phosphorylation in Mammals: Regulation, Protein Targets, and Biology
哺乳动物中的组氨酸磷酸化:调节、蛋白质靶点和生物学
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9330534 - 财政年份:2016
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TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
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8541082 - 财政年份:2012
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TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
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8218480 - 财政年份:2012
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TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
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