Metabolic consequences of cystinuria and genome engineering therapeutics
胱氨酸尿症和基因组工程疗法的代谢后果
基本信息
- 批准号:9898319
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAmino AcidsAnimalsArginineBiological AssayBloodBlood PressureCRISPR/Cas technologyCellsChronicChronic Kidney FailureClinicalComplementary DNACystineCystinuriaDNADependovirusDevelopmentDietDiseaseEngineeringExhibitsExperimental DesignsFundingGene DeliveryGene ExpressionGene MutationGene TargetingGene TransferGenesGeneticGenomeGenome engineeringGrantGuide RNAHealthHumanHybridsHypertensionImmunosuppressionIn VitroInheritedInjury to KidneyKidneyKidney CalculiKidney DiseasesKnock-outLiverLysineMediatingMedicalMetabolicMethodsMissionModelingMorbidity - disease rateMusMutationNeonatalNephrolithiasisOrnithinePatientsPhenotypePlaguePlasmaProteinsPublishingRecoveryReduced GlutathioneReperfusion InjuryResearchSolubilitySystemTechnologyTechnology TransferTestingTherapeuticThioctic AcidTranscription CoactivatorTransposaseTubular formationUreteral obstructionUrineVariantVeteransadeno-associated viral vectoramino acid metabolismbasegene correctiongenome editinghuman diseaseimprovedin vivoinnovationmolecular targeted therapiesmouse modelnon-viral gene deliverypreventresponseside effecturinaryvector
项目摘要
ABSTRACT
Cystinuria is an inherited human renal disease with significant morbidity affecting 1 in 7000 veterans. The
disease is caused by mutation of genes involved in renal cystine transport resulting in elevated urinary cystine
with kidney stone formation. Historically, the primary clinical concern of cystinuria has been that cystine spills
into the urine resulting in nephrolithiasis. However, cystinuria patients develop more chronic kidney disease and
hypertension than other stone formers. Additionally, little is known about other consequences of loss of amino
acid transport function (of cystine, ornithine, lysine, and arginine). These additional metabolic consequences of
cystinuria likely contribute to the observations that cystinuria patients develop more chronic kidney and
hypertension compared to other kidney stone formers. With the genetic basis of the disorder defined (mutation
in Slc3a1, cystinuria type I), opportunities for targeted molecular therapies exist. Building upon our previous
grant, we propose an innovative experimental design to demonstrate long-term phenotypic correction of
cystinuria in an intact animal using a combination of transposon, adeno-associated virus (AAV), and
CRISPR/Cas9 genome engineering technologies.
In specific aim 1, we will evaluate the effects of the metabolic changes on sensitivity to and recovery from kidney
injury and the development of hypertension. We will use ischemia reperfusion injury models and the unilateral
ureteral obstruction to evaluate sensitivity to and recovery from kidney injury. We will also evaluate whether α-
lipoic acid has any effect on these metabolic consequences other than its known ability to increase the solubility
of cystine in the urine and prevent cystine stone formation. In specific aim 2, we propose to engineer a chimeric
piggyBac transposase capable of rescuing of Slc3a1 expression and we will compare this to CRISPR/Cas9
mediated targeted integration in mouse proximal tubular cells lacking Slc3a1. We also propose to attempt
permanent correction of cystinuria in vivo by multiple genome engineering technologies including transposon
technology with concomitant immunosuppression, hybrid AAV-transposon technology and CRISPR/Cas9
mediated genome editing or targeted integration. We will attempt correction both in neonatal and adult mice
lacking Slc3a1 assaying for reduction of cystine level in the urine, increase of cystine level in the plasma, and
reduction of cystine stones. The proposed studies will lead to a greater understanding of the metabolic
consequences of cystinuria and develop genome engineering approaches for cystinuria and potentially other
kidney diseases affecting veterans.
摘要
胱氨酸尿症是一种遗传性人类肾脏疾病,发病率高,每7000名退伍军人中就有1人患病。的
疾病是由参与肾胱氨酸转运的基因突变引起的,导致尿胱氨酸升高
肾结石的形成。从历史上看,胱氨酸尿症的主要临床问题是胱氨酸溢出
进入尿液导致肾结石然而,胱氨酸尿症患者发展为更多的慢性肾病,
高血压比其他结石形成者。此外,对氨基丢失的其他后果知之甚少。
酸转运功能(胱氨酸、鸟氨酸、赖氨酸和精氨酸)。这些额外的代谢后果
胱氨酸尿症可能有助于观察到胱氨酸尿症患者发生更多的慢性肾功能衰竭,
高血压与其他肾结石形成者相比。随着疾病的遗传基础的定义(突变
在Slc 3a 1,胱氨酸尿症I型)中,存在靶向分子治疗的机会。基于我们之前的
格兰特,我们提出了一个创新的实验设计,以证明长期的表型校正
使用转座子、腺相关病毒(AAV)和
CRISPR/Cas9基因组工程技术。
在具体目标1中,我们将评估代谢变化对肾脏敏感性和恢复的影响。
损伤和高血压的发展。采用缺血再灌注损伤模型,
输尿管梗阻,以评估肾损伤的敏感性和恢复情况。我们还将评估α-
除了已知的增加溶解度的能力之外,
尿中的胱氨酸,防止胱氨酸结石的形成。在具体目标2中,我们提出工程化嵌合体,
piggyBac转座酶能够拯救Slc 3a 1表达,我们将其与CRISPR/Cas9进行比较
在缺乏Slc 3a 1的小鼠近端肾小管细胞中介导的靶向整合。我们还建议尝试
通过包括转座子在内的多种基因组工程技术在体内永久纠正胱氨酸尿症
伴随免疫抑制的技术、杂合AAV转座子技术和CRISPR/Cas9
介导的基因组编辑或靶向整合。我们将尝试在新生小鼠和成年小鼠中进行校正
缺乏Slc 3a 1测定尿中胱氨酸水平的降低、血浆中胱氨酸水平的增加,和
减少胱氨酸结石。拟议的研究将导致更好地了解代谢
胱氨酸尿症的后果,并开发胱氨酸尿症的基因组工程方法和潜在的其他
影响退伍军人的肾病
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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MATTHEW H WILSON其他文献
MATTHEW H WILSON的其他文献
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{{ truncateString('MATTHEW H WILSON', 18)}}的其他基金
Next generation transposon vectors for genome engineering
用于基因组工程的下一代转座子载体
- 批准号:
10688194 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Next generation transposon vectors for genome engineering
用于基因组工程的下一代转座子载体
- 批准号:
10501335 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Metabolic consequences of cystinuria and genome engineering therapeutics
胱氨酸尿症和基因组工程疗法的代谢后果
- 批准号:
10265368 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Genome engineering therapeutics for cystinuria and its metabolic consequences.
胱氨酸尿症的基因组工程疗法及其代谢后果。
- 批准号:
10588590 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Kidney specific site-directed integration for cystinuria
肾脏特异性定点整合治疗胱氨酸尿症
- 批准号:
8542365 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Novel cell therapy for sustained therapeutic protein delivery in vivo
用于体内持续治疗性蛋白质递送的新型细胞疗法
- 批准号:
10428544 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Novel cell therapy for sustained therapeutic protein delivery in vivo
用于体内持续治疗性蛋白质递送的新型细胞疗法
- 批准号:
10011826 - 财政年份:2012
- 资助金额:
-- - 项目类别:
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