Irreversible Inhibtion of Cerebellar Gli Transcription Factors by Cobalt (III) Complexes
钴 (III) 复合物对小脑 Gli 转录因子的不可逆抑制
基本信息
- 批准号:10338124
- 负责人:
- 金额:$ 2.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-01 至 2022-07-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAdverse effectsAgeAlkynesAzidesBindingCancer EtiologyCell Membrane PermeabilityCellsChildChildhood Malignant Brain TumorClinical TrialsCobaltComplexConsensus SequenceContrast MediaCoupledCouplingDNADNA Binding DomainDNA StructureDevelopmental Delay DisordersDiseaseDoseDrosophila genusDrug resistanceEffectivenessEmbryoEnsureErinaceidaeExcisionFamilyGLI Family ProteinGenesGeneticGenetic TranscriptionGoalsGrowthHeterogeneityHistologyHomologous GeneHumanHybridsImageImpairmentIn VitroIndividualInjectionsInvestigationKnowledgeLabelLaboratoriesLeadLigand BindingLigandsMagnetic Resonance ImagingMalignant - descriptorMembrane ProteinsMethodsMissionModelingMutationNanoconjugateOutcomePathway interactionsPatientsPhysiologicalPropertyProteinsQuality of lifeResearchRouteSHH geneSchemeSchiff BasesSeriesSiteSpecificitySubgroupSurvival RateSystemTemperatureUnited States National Institutes of HealthZinc Fingerscancer imagingcancer recurrencechemotherapyeffective therapyexperienceimprovedin vivoindividualized medicineinhibitorinterestirradiationkidney cellmedulloblastomamedulloblastoma cell linemortalitymouse modelnanoGoldnanoparticle deliverypreservationresistance mutationscaffoldsmoothened signaling pathwaystemsuccesstranscription factortreatment strategytumortumor growthuptake
项目摘要
Aberrant expression of the Hedgehog (Hh) signaling pathway is heavily implicated in the formation and
proliferation of a subgroup of medulloblastoma (MB) tumors. MB is predominantly a pediatric brain cancer, with
70% of occurrences appearing in children under the age of 10. The SHH subgroup, driven by Hh signaling, is
widely heterogeneous in genetic cause and histology, making effective treatment challenging and resulting in
dismal outcomes. Current treatment strategies involve tumor resection, craniospinal irradiation, and
chemotherapy, but suffer from short-term and long-term adverse effects. In efforts to inhibit the Hh pathway,
research has targeted the protein Smoothened (Smo), but has been stunted by downstream mutations that
lead to cancer recurrence with a much higher lethality. Thus, this project seeks to target Gli proteins, which
belong to a family of zinc finger transcription factors (TFs) and are the final effectors of the Hh pathway. The
Meade lab has developed a series of Cobalt (III)-Schiff base complexes (Co(III)-sb) coupled to TF consensus
sequences that specifically and irreversibly inhibit zinc finger TFs of interest. This proposal seeks to reinvent
the method for conjugating Co(III)-sb to the Gli consensus sequence to generate Co(III)-Gli, a highly specific
and irreversible inhibitor of Gli proteins. This inhibitor will be conjugated to a Gd(III)-labeled gold nanoparticle
(AuNP) delivery platform to evaluate and image the effectiveness of Gli inhibition both in vitro and in vivo.
The first objective of this proposal is to redesign the synthetic route for coupling DNA to Co(III)-sb. The
equatorial ligand scaffold of Co(III)-sb will be functionalized with an alkyne moiety to allow for clickable
conjugation to an azide functionalized Gli consensus sequence, generating Co(III)-Gli. This is anticipated to
significantly improve yields and scalability from the current conjugation method. The second and third
objectives focus on evaluating the potency of Co(III)-Gli against Gli for the inhibition of tumor growth. Co(III)-Gli
will be hybridized to a DNA capped AuNP to generate an optimized dehybridization sequence to release the
agent at physiological temperature. Co(III)-Gli AuNPs will be labeled with Gd(III) magnetic resonance imaging
(MRI) contrast agents to provide a platform for fate mapping the conjugates both in vitro and in vivo. The ability
of Co(III)-Gli to inhibit exogenous Gli will be evaluated in vitro using human embryonic kidney cells and in vivo
using a murine model that natively develops SHH subtype MB tumors. Co(III)-Gli is anticipated to inhibit Gli
with high specificity, resulting in suppressed tumor growth.
This project fully aligns with the mission of the NIH both in its short-term and long-term implications. It
will further develop knowledge about inhibition of cerebellar Gli transcription factors in the short-term, and
generate a platform for enhancing current treatment options for SHH subtype medulloblastoma long-term. The
success of this project would present a unique opportunity for improving the survival rate and resulting quality
of life for the most malignant childhood brain cancer.
Hedgehog (Hh)信号通路的异常表达与肿瘤的形成和发育密切相关
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Meghan Ward其他文献
Meghan Ward的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 2.4万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 2.4万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 2.4万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 2.4万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
Studentship














{{item.name}}会员




