Pediatric Heart Disease: Getting from Mutations to Therapeutics
小儿心脏病:从突变到治疗
基本信息
- 批准号:9440083
- 负责人:
- 金额:$ 1.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-28 至 2017-09-30
- 项目状态:已结题
- 来源:
- 关键词:ADME StudyAddressAdoptedAdultAdverse effectsAnimalsBackBiologicalBiological ModelsCardiacCardiovascular DiseasesCaringCell LineCell modelCellsChemicalsChildhoodClinical Trials DesignComorbidityComplexCongenital Heart DefectsDataDevelopmentDiseaseDisease modelDrosophila genusDrosophila melanogasterDrug InteractionsDrug usageEyeFDA approvedGeneticGenomicsHeart DiseasesHeart HypertrophyHereditary DiseaseHomeostasisHumanHypertrophic CardiomyopathyLibrariesMethodsMissionMitogen-Activated Protein KinasesModelingMutant Strains MiceMutationMyocardialNational Heart, Lung, and Blood InstituteNoonan SyndromeOther GeneticsPathogenesisPharmaceutical PreparationsPharmacogenomicsPharmacologyPhenotypePlant RootsPremature MortalityPupaRAF1 geneResearch PersonnelRoboticsSignal TransductionSystemTechnologyTestingTherapeuticToxic effectVeinsVial deviceWingaccurate diagnosisbasedisease-causing mutationdrug developmentflygene discoveryhigh throughput screeningimprovedinduced pluripotent stem cellinterestmouse modelmutantnovel therapeuticsprognosticscreeningsmall moleculesmall molecule librariestrait
项目摘要
Pediatric cardiovascular disorders, which comprise congenital heart defects (CHD) and myocardial and
conduction system diseases, remain highly challenging due to cardiac co-morbidities and premature mortality.
As most of these disorders are genetic, efforts over the past 30 years have focused on identifying their causal
mutations. Particularly for Mendelian traits such as Noonan syndrome and related disorders (the
RASopathies), this has been highly successful. Newer genomic technologies have accelerated gene discovery
for pediatric cardiovascular disorders, including genetically complex ones. These genetic discoveries are
improving care through more accurate diagnosis, better prognostication, and refinement of clinical trial design.
What has not occurred with rare exception is the development of novel therapies based on the new
understanding of disease pathogenesis enabled by these gene discoveries. Finding therapies for
pediatric cardiovascular disorders will be challenging because the biological targets are generally central to cell
homeostasis (e.g., RAS/MAP kinase signaling) so cannot be completely inhibited for long periods without
incurring side effects that would outweigh their benefits. For this R35 mechanism, I and my outstanding co-
investigators with relevant expertise intend to address this gap using a drug development pipeline that begins
with high-throughput screening to overcome pupal lethality in Drosophila melanogaster models of disease with
a chemical library that covers druggable space (n=14,400) using 96-well plates and robotics. Screening in
whole animals is performed agnostically and has the putative advantage of providing a simultaneous read out
of efficacy and toxicity. We provide preliminary data showing that we have already achieved this using a fly
RAF1 mutant model of Noonan syndrome with hypertrophic cardiomyopathy. Subsequent steps with fruit flies
include confirmation of initial hits in vials, determining efficacy against adult fly phenotypes such as rough eye,
ectopic wing veins and heart hypertrophy. Back-up libraries for the candidate compounds, typically 60-80
chemical neighbors, will be culled for ones with most desirable drug traits and then screened in the fly models.
Using a defined set of fruit fly deficiency lines, targets and anti-targets will be established to enable further
rounds of rational pharmacology. ADME studies will be used to reduce potential for drug-drug interactions. In
parallel, we will pursue repurposing of FDA-approved drugs using library screening with fruit fly models and
systems pharmacogenomics. Leading compounds and drugs will then be tested against phenotypes in human
induced pluripotent stem cell lines with the disease-causing mutation for efficacy. The most promising drugs
will then be tested in existing mouse models (e.g., HCM in Raf1 mutant mice) using appropriate endpoints.
Taken as a whole, the approach proposed will significantly advance the identification of novel therapeutics for
pediatric cardiovascular diseases, starting with the RASopathies and later for other traits. If robust, this will
provide a paradigm that can be adopted for other genetic traits of interest to the NHLBI.
儿科心血管疾病,包括先天性心脏缺陷(CHD)和心肌和
传导系统疾病由于心脏合并症和过早死亡而仍然具有高度挑战性。
由于大多数这些疾病是遗传性的,过去30年的努力集中在确定其病因上。
突变。特别是对于孟德尔性状,如努南综合征和相关疾病(
),这是非常成功的。更新的基因组技术加速了基因发现
用于儿科心血管疾病,包括遗传复杂的疾病。这些基因发现是
通过更准确的诊断、更好的诊断和完善的临床试验设计来改善护理。
除了罕见的例外,还没有出现的是基于新的治疗方法的发展。
这些基因的发现使人们对疾病发病机制的理解成为可能。寻找治疗方法
儿科心血管疾病将是具有挑战性的,因为生物靶点通常是细胞的中心,
稳态(例如,RAS/MAP激酶信号传导),因此不能长时间完全抑制,
带来的副作用会超过它们的好处。对于这个R35机制,我和我杰出的合作伙伴-
具有相关专业知识的研究人员打算使用药物开发管道来解决这一差距,
通过高通量筛选克服果蝇疾病模型中的蛹致死性,
使用96孔板和机器人技术,覆盖可药用空间的化学品库(n= 14,400)。筛查
整个动物是不可知的,并且具有提供同时读出的假定优势
有效性和毒性。我们提供的初步数据表明,我们已经实现了这一点,
伴有肥厚型心肌病的努南综合征RAF 1突变模型果蝇的后续步骤
包括在小瓶中确认初始命中,确定对成蝇表型如粗眼的功效,
异位翼静脉和心脏肥大候选化合物的备份库,通常为60-80
化学邻居,将被淘汰的最理想的药物性状,然后在苍蝇模型筛选。
使用一组确定的果蝇缺陷系,将建立靶标和抗靶标,以使得能够进一步进行基因治疗。
一轮轮的理性药理学。ADME研究将用于降低药物间相互作用的可能性。在
与此同时,我们将利用果蝇模型库筛选,对FDA批准的药物进行再利用,
系统药物基因组学然后将针对人类的表型测试主要化合物和药物。
具有致病突变的诱导多能干细胞系用于功效。最有前途的药物
然后将在现有的小鼠模型中进行测试(例如,Raf 1突变小鼠中的HCM)。
总的来说,所提出的方法将显著推进新疗法的鉴定,
儿科心血管疾病,从RASopathies开始,后来用于其他特征。如果健壮,这将
为NHLBI感兴趣的其他遗传性状提供了一个范例。
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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{{ truncateString('BRUCE D GELB', 18)}}的其他基金
Incorporating genomics into the clinical care of diverse NYC children
将基因组学纳入纽约市不同儿童的临床护理中
- 批准号:
10361994 - 财政年份:2021
- 资助金额:
$ 1.93万 - 项目类别:
Pediatric Heart Disease: Getting from Mutations to Therapeutics
小儿心脏病:从突变到治疗
- 批准号:
9241613 - 财政年份:2017
- 资助金额:
$ 1.93万 - 项目类别:
Pediatric Heart Disease: Getting from Mutations to Therapeutics
小儿心脏病:从突变到治疗
- 批准号:
10549344 - 财政年份:2017
- 资助金额:
$ 1.93万 - 项目类别:
Pediatric Heart Disease: Getting from Mutations to Therapeutics
小儿心脏病:从突变到治疗
- 批准号:
10112285 - 财政年份:2017
- 资助金额:
$ 1.93万 - 项目类别:
Pediatric Heart Disease: Getting from Mutations to Therapeutics
小儿心脏病:从突变到治疗
- 批准号:
9894834 - 财政年份:2017
- 资助金额:
$ 1.93万 - 项目类别:
Human Induced Pluripotent Cell Models of Pediatric Cardiac Disorders
人类诱导的小儿心脏病多能细胞模型
- 批准号:
8583749 - 财政年份:2013
- 资助金额:
$ 1.93万 - 项目类别:
Human Induced Pluripotent Cell Models of Pediatric Cardiac Disorders
人类诱导的小儿心脏病多能细胞模型
- 批准号:
8774293 - 财政年份:2013
- 资助金额:
$ 1.93万 - 项目类别:
Human Induced Pluripotent Cell Models of Pediatric Cardiac Disorders
人类诱导的小儿心脏病多能细胞模型
- 批准号:
8704996 - 财政年份:2013
- 资助金额:
$ 1.93万 - 项目类别:
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