Generating transplantable neurons by in vivo combinatorial screening of transcrip
通过体内转录组合筛选产生可移植神经元
基本信息
- 批准号:8508325
- 负责人:
- 金额:$ 77.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-30 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAnimalsBiologicalBiological AssayBrainCell LineageCell TransplantsCellsChemicalsClinicalClinical TrialsCuesDegenerative DisorderDiseaseEpilepsyEvaluationEye diseasesGeneticHumanHuntington DiseaseIn VitroIndividualLaboratoriesMediatingMethodologyModificationMolecularNeuronal InjuryNeuronsParkinson DiseasePhysical therapyPreparationProcessRNARecovery of FunctionRodentSignal TransductionSiteSolutionsStagingStrokeSymptomsTechnologyTestingTissue TransplantationTissuesTransplantationXenograft procedureaging populationcell typecombinatorialfetalfunctional improvementhigh throughput screeningin vivoinduced pluripotent stem cellinnovationneuronal growthneuronal survivalnuclear reprogrammingrelease factorresearch studyrestorationretina transplantationscreeningsynaptogenesistranscription factor
项目摘要
Problem: Neuronal injuries, degenerative diseases, and disorders such as Parkinson¿s and Huntington¿s diseases, epilepsy, and stroke affect tens of millions of individuals in the USA alone, and are becoming a more severe problem with the aging population. Although significant effort is being invested for identification of the molecular processes involved, existing chemical and physical therapies do not promise restoration of lost neuronal circuits beyond the short term remedy of symptoms. A potential solution could be the use of tissue transplantation to restore neuronal function. There have been human trials where transplantations, although variably, have resulted in functional recovery in Parkinson¿s (PD) and Huntington¿s (HD) diseases. Cell replacement for epilepsy and stroke has shown promise in several rodent studies, and the transplantation of retinal cells to treat degenerative eye diseases is under evaluation in several laboratories. Although there are still many unknowns, in various cases, it has been observed that functional improvements occurred owing to the integration of grafted neurons into existing neuronal networks, and was not simply due to trophic factors released by the transplanted cells. Several studies have also shown that the adult brain is remarkably capable of providing signaling cues that guide the growth of neuronal processes and induce formation of synapses with desired targets when correct cell types are present within the grafts. Xenograft studies with animals larger than rodents have shown that these cues can function over long distances. However, while tissue transplantation may have significant potential, there are many scientific unknowns and several fundamental challenges exist as outlined in this proposal. Handling complexity of these challenges is currently beyond the capabilities of the largest laboratories in the world, and will likely require deployment of systematic high-throughput approaches that will not only address fundamental biological questions and rapidly test various hypotheses without bias, but also provide results that are, if promising, translatable to clinical trials. Challenges: (1) Human fetal or iPS-derived cells are either too scarce or tumorogenic for clinical use, (2) Transplanted cells are too heterogeneous, (3) Preparation of transplanted cells in the correct and synchronized stages is currently impossible, (4) Physical site of transplantation significantly varies from experiment to experiment, (5) Existing in vivo transplantation assays are too slow for screening of multitudes of different hypotheses. Innovation & Methodology: Here, we propose a systematic, unbiased, in vivo, large-scale, and high throughput approach for overcoming these challenges to in vitro differentiation and in vivo testing of transplanted neuronal tissues. The proposed methodologies here are applicable to most transplantation paradigms. The key technologies and strategies we will develop include: (A) RNA-mediated nuclear reprogramming without genetic modification, (B) Reprogramming human cell lineages by systematic ultra-high-throughput screening of RNA transcription factor cocktails using a massively parallel technology, (C) High-throughput transplantation of human cells into rodents (with minimal rodent sacrifice) and in vivo analysis of neuronal survival and integration.
问题:仅在美国,神经元损伤、退行性疾病和诸如帕金森氏病和亨廷顿氏病、癫痫和中风的病症就影响数千万个体,并且随着人口老龄化正成为更严重的问题。虽然正在投入大量的努力来鉴定所涉及的分子过程,但现有的化学和物理疗法除了短期治疗症状外,不能保证恢复丢失的神经元回路。一个潜在的解决方案可能是使用组织移植来恢复神经元功能。在人体试验中,移植虽然效果不佳,但已导致帕金森病(PD)和亨廷顿病(HD)的功能恢复。癫痫和中风的细胞替代在几项啮齿动物研究中显示出希望,视网膜细胞移植治疗退行性眼病正在几个实验室进行评估。尽管仍有许多未知数,但在各种情况下,已观察到由于移植神经元整合到现有神经元网络中而发生的功能改善,而不仅仅是由于移植细胞释放的营养因子。几项研究还表明,当移植物中存在正确的细胞类型时,成人大脑显著能够提供引导神经元过程生长并诱导与所需靶点形成突触的信号线索。对比啮齿动物大的动物进行的异种移植研究表明,这些线索可以在长距离内发挥作用。然而,尽管组织移植可能具有巨大的潜力,但仍存在许多科学未知数,并且存在本提案中概述的几个根本挑战。处理这些挑战的复杂性目前超出了世界上最大的实验室的能力,并且可能需要部署系统的高通量方法,不仅解决基本的生物学问题并快速无偏差地测试各种假设,而且还提供结果,如果有希望的话,可以转化为临床试验。挑战:(1)人类胎儿或iPS衍生的细胞对于临床应用而言太稀少或致瘤,(2)移植的细胞太异质,(3)在正确和同步的阶段制备移植的细胞目前是不可能的,(4)移植的物理部位在实验与实验之间显著变化,(5)现有的体内移植试验对于筛选大量不同的假设来说太慢。创新与方法:在这里,我们提出了一个系统的,公正的,在体内,大规模,高通量的方法,克服这些挑战,在体外分化和移植的神经元组织的体内测试。这里提出的方法适用于大多数移植范例。我们将开发的关键技术和策略包括:(A)RNA介导的核重编程,而无需遗传修饰,(B)使用大规模平行技术通过系统性超高通量筛选RNA转录因子鸡尾酒来重编程人类细胞谱系,(C)将人类细胞高通量移植到啮齿动物中(以最小的啮齿动物牺牲)并在体内分析神经元存活和整合。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Mehmet Fatih Yanik其他文献
Functional regeneration after laser axotomy
激光轴突切断后的功能性再生
- DOI:
10.1038/432822a - 发表时间:
2004-12-15 - 期刊:
- 影响因子:48.500
- 作者:
Mehmet Fatih Yanik;Hulusi Cinar;Hediye Nese Cinar;Andrew D. Chisholm;Yishi Jin;Adela Ben-Yakar - 通讯作者:
Adela Ben-Yakar
Verfahren zur zelltransfektion mit nukleinsäuren
核转移的影响
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Mehmet Fatih Yanik;Matthew Angel - 通讯作者:
Matthew Angel
Deep-learning-based identification, tracking, pose estimation and behaviour classification of interacting primates and mice in complex environments
基于深度学习的复杂环境中相互作用的灵长类动物和小鼠的识别、跟踪、姿势估计和行为分类
- DOI:
10.1038/s42256-022-00477-5 - 发表时间:
2022-04-21 - 期刊:
- 影响因子:23.900
- 作者:
Markus Marks;Qiuhan Jin;Oliver Sturman;Lukas von Ziegler;Sepp Kollmorgen;Wolfger von der Behrens;Valerio Mante;Johannes Bohacek;Mehmet Fatih Yanik - 通讯作者:
Mehmet Fatih Yanik
Mehmet Fatih Yanik的其他文献
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{{ truncateString('Mehmet Fatih Yanik', 18)}}的其他基金
Generating transplantable neurons by in vivo combinatorial screening of transcrip
通过体内转录组合筛选产生可移植神经元
- 批准号:
8337690 - 财政年份:2011
- 资助金额:
$ 77.84万 - 项目类别:
Generating transplantable neurons by in vivo combinatorial screening of transcrip
通过体内转录组合筛选产生可移植神经元
- 批准号:
8142682 - 财政年份:2011
- 资助金额:
$ 77.84万 - 项目类别:
Generating transplantable neurons by in vivo combinatorial screening of transcrip
通过体内转录组合筛选产生可移植神经元
- 批准号:
8912552 - 财政年份:2011
- 资助金额:
$ 77.84万 - 项目类别:
Generating transplantable neurons by in vivo combinatorial screening of transcrip
通过体内转录组合筛选产生可移植神经元
- 批准号:
8712586 - 财政年份:2011
- 资助金额:
$ 77.84万 - 项目类别:
HIGH-THROUGHPUT IN VIVO SUBCELLULAR-RESOLUTION VERTEBRATE SCREENING PLATFORM
高通量体内亚细胞分辨率脊椎动物筛选平台
- 批准号:
8268464 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
HIGH-THROUGHPUT IN VIVO SUBCELLULAR-RESOLUTION VERTEBRATE SCREENING PLATFORM
高通量体内亚细胞分辨率脊椎动物筛选平台
- 批准号:
8660716 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
HIGH-THROUGHPUT IN VIVO SUBCELLULAR-RESOLUTION VERTEBRATE SCREENING PLATFORM
高通量体内亚细胞分辨率脊椎动物筛选平台
- 批准号:
8477325 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
HIGH-THROUGHPUT IN VIVO SUBCELLULAR-RESOLUTION VERTEBRATE SCREENING PLATFORM
高通量体内亚细胞分辨率脊椎动物筛选平台
- 批准号:
8150903 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
HIGH-THROUGHPUT IN VIVO SUBCELLULAR-RESOLUTION VERTEBRATE SCREENING PLATFORM
高通量体内亚细胞分辨率脊椎动物筛选平台
- 批准号:
8016924 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
High-throughput single-cell-resolution genetic and pharmacological screens using
高通量单细胞分辨率遗传和药理学筛选
- 批准号:
8053299 - 财政年份:2009
- 资助金额:
$ 77.84万 - 项目类别:
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