Testing brain penetrant iron chelators and investigating putative clearance pathway in ICH
测试脑渗透铁螯合剂并研究 ICH 中假定的清除途径
基本信息
- 批准号:10201369
- 负责人:
- 金额:$ 38.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAdultAffinityAftercareAlbuminsAnatomyAnimalsAttenuatedAutologousBilirubinBindingBloodBlood gasBrainBrain EdemaBrain hemorrhageC57BL/6 MouseCD3 AntigensCD36 geneCarboxylic AcidsCell DeathCellsCerebral hemisphere hemorrhageChelating AgentsChemistryClinical TrialsCremophorCytolysisDataDeferoxamineDoseEnzyme-Linked Immunosorbent AssayEnzymesErythrocytesEthylenediaminesFemaleFutureGlial Fibrillary Acidic ProteinGliosisGlucoseGoalsH ferritinHalf-LifeHematocrit procedureHematomaHemoglobinHemoglobin concentration resultHemorrhageHomeostasisHumanHydroxyl RadicalIn Situ Nick-End LabelingIndividualInflammationInflammatoryInjectionsInjuryInternationalIronIron Chelating AgentsKnock-outKnowledgeLeadLiteratureLiverMeasuresMedicalMitochondriaModelingMonitorMotorMusNeuroanatomyNeuronsOperative Surgical ProceduresOrganOutcomeOxidative StressPathogenesisPathologyPathway interactionsPhagocytesPharmaceutical PreparationsPhasePhysiologicalPlasmaPre-Clinical ModelProcessProdrugsReaction TimeRegimenRoleSafetySecondary toSerumSerum iron level resultStressStrokeTestingTherapeuticThiazolesTimeToxic effectTraumatic Brain InjuryWhite Blood Cell Count procedureanalogbasebrain cellclinical investigationcompare effectivenessdesigneffective therapyefficacy testingexperimental studyfluoro jadeforced swim testheme oxygenase-1improvedinnovationlipophilicitymalemortalitynephrotoxicityneurobehavioralnoveloutcome forecastphase III trialpreventprimary outcomeprolyl-prolinereceptorresponsesecondary outcomestroma free hemoglobinsymposiumtherapeutic targettool
项目摘要
Intracerebral hemorrhage (ICH) is a serious medical condition caused by bleeding in the brain. It should be noted
that at the last AHA/ASA International Stroke Conference in Feb. 2019, findings were presented from a Phase
III trial showing that deferoxamine (DFO) was futile against ICH. One potential explanation is that DFO does not
cross the BBB, and it has significant toxicity issues. Thus, the main focus now is to determine the efficacy and
therapeutic window of a novel, safe, and effective therapy against ICH by testing unique brain penetrant iron
chelators. To achieve this goal, and based on the literature and our preliminary data, we will test potent and
selective iron chelators such as HBED, and their efficacy will be compared to other iron chelators such as the
DADMDFT analog and DFO.
After intracranial bleeding, red blood cells lyse and release large amounts of hemoglobin (Hb). These have to
be actively phagocytosed, after which the heme (which cannot be recycled) gets degraded to generate iron
intracellularly. Under normal physiological conditions, iron homeostasis should be maintained; however, when
there are too many (heme) substrates, there is also too much iron, a process called iron dyshomeostasis. Our
overall hypothesis is that a lipophilic brain penetrant iron chelator would be effective against ICH. Notably, HBED
also has a much better safety profile compared to DFO, which was noted after a thorough Phase I safety trial.
We observed that HBED was most potent after a traumatic brain injury model. Also, we found that DADMDFT
provides benefits by improving functional and anatomical outcomes in the stroma-free Hb injection model.
Besides binding iron, HBED binds ferrous (toxic) iron and converts it into ferric (nontoxic) iron in cells and
mitochondria, preventing prooxidant and proinflammatory cascades.
Aim 1 is to investigate the efficacy of HBED over DADMDFT and DFO in improving neurobehavioral and
anatomical outcomes after ICH. We will determine and compare the optimal dose-response and therapeutic
window of HBED, DADMDFT, and DFO in adult male mice and in parallel in females. Aims 2, 3, and 4 are to
investigate the importance of the known phagocytic receptors CD36 and CD163 for RBCs and Hb, respectively,
using the autologous blood ICH preclinical model. We will use the single and double knockouts (versus matched
C57BL/6 littermates) that we have already generated. The goal is to understand mechanistically the respective
role of these phagocytic receptors because they should participate in the clearance of RBCs and hemoglobin
and test the added benefits of the optimal iron chelator, helping to limit the oxidative/inflammatory stress
cascades. Toxicity will be monitored, along with brain and serum iron levels over time, after treatment with the
iron chelator.
This project is timely, and we believe we have assembled a unique team with the tools, animals, models, and
expertise necessary to rigorously perform these experiments. We are confident that we can accomplish the
proposed aims to inform our stroke partners, allowing them to design a rigorous clinical trial.
脑内出血(ICH)是由脑部出血引起的一种严重疾病。应当注意
在2019年2月举行的上一届AHA/阿萨国际卒中会议上,
III期试验显示去铁胺(DFO)对ICH无效。一个潜在的解释是DFO不
穿过血脑屏障,并且具有显著的毒性问题。因此,现在的主要焦点是确定疗效和
通过测试独特的脑渗透铁,确定一种新型、安全、有效的ICH治疗方法的治疗窗
螯合剂。为了实现这一目标,并根据文献和我们的初步数据,我们将测试有效和
选择性铁螯合剂,如HBED,并且它们的功效将与其他铁螯合剂,
DADMDFT模拟和DFO。
颅内出血后,红细胞溶解并释放大量血红蛋白(Hb)。这些都必须
被积极吞噬,之后血红素(不能回收)被降解产生铁
细胞内。在正常的生理条件下,铁稳态应该维持;然而,当
有太多的(血红素)底物,也有太多的铁,一个过程称为铁稳态失调。我们
总的假设是亲脂性脑渗透铁螯合剂对ICH有效。值得注意的是,HBED
也有更好的安全性相比,DFO,这是指出后,彻底的第一阶段的安全性试验。
我们观察到HBED在创伤性脑损伤模型后是最有效的。我们还发现,
通过改善无基质Hb注射模型中的功能和解剖结果提供益处。
除了结合铁,HBED结合亚铁(有毒)铁,并将其转化为细胞中的三价铁(无毒)铁,
线粒体,防止促氧化剂和促炎级联反应。
目的1:比较HBED与DADMDFT和DFO在改善神经行为和神经功能方面的疗效,
脑出血后的解剖学结局。我们将确定和比较最佳剂量反应和治疗
在成年雄性小鼠和雌性小鼠中平行观察HBED、DADMDFT和DFO的窗口。目标2、3和4是:
研究已知的吞噬细胞受体CD 36和CD 163分别对RBC和Hb的重要性,
使用自体血液ICH临床前模型。我们将使用单和双淘汰赛(与匹配
C57 BL/6同窝仔)。目标是从机械上理解
这些吞噬受体的作用,因为它们应该参与清除红细胞和血红蛋白
并测试最佳铁螯合剂的额外益处,有助于限制氧化/炎症应激
瀑布在用本发明的化合物治疗后,将监测毒性,沿着脑和血清铁水平随时间的变化。
铁螯合剂
这个项目是及时的,我们相信我们已经组建了一个独特的团队与工具,动物,模型,
严格执行这些实验所需的专业知识。我们有信心,我们可以完成
建议的目的是通知我们的中风合作伙伴,让他们设计一个严格的临床试验。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease.
- DOI:10.3390/ijms22126408
- 发表时间:2021-06-15
- 期刊:
- 影响因子:5.6
- 作者:Ashouri R;Fangman M;Burris A;Ezenwa MO;Wilkie DJ;Doré S
- 通讯作者:Doré S
Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes.
- DOI:10.3389/fneur.2021.670245
- 发表时间:2021
- 期刊:
- 影响因子:3.4
- 作者:Ashouri R;Fangman M;Brielmaier J;Fields ZA;Campo N;Doré S
- 通讯作者:Doré S
Genome-Wide Association Study of Clinical Outcome After Aneurysmal Subarachnoid Haemorrhage: Protocol.
- DOI:10.1007/s12975-021-00978-2
- 发表时间:2022-08
- 期刊:
- 影响因子:6.9
- 作者:Gaastra, Ben;Alexander, Sheila;Bakker, Mark K.;Bhagat, Hemant;Bijlenga, Philippe;Blackburn, Spiros;Collins, Malie K.;Dore, Sylvain;Griessenauer, Christoph;Hendrix, Philipp;Hong, Eun Pyo;Hostettler, Isabel C.;Houlden, Henry;IIhara, Koji;Jeon, Jin Pyeong;Kim, Bong Jun;Kumar, Munish;Morel, Sandrine;Nyquist, Paul;Ren, Dianxu;Ruigrok, Ynte M.;Werring, David;Galea, Ian;Bulters, Diederik;Tapper, Will
- 通讯作者:Tapper, Will
Effects of Sound Interventions on the Permeability of the Blood-Brain Barrier and Meningeal Lymphatic Clearance.
- DOI:10.3390/brainsci12060742
- 发表时间:2022-06-05
- 期刊:
- 影响因子:3.3
- 作者:
- 通讯作者:
Potential Role of Soluble Toll-like Receptors 2 and 4 as Therapeutic Agents in Stroke and Brain Hemorrhage.
- DOI:10.3390/ijms22189977
- 发表时间:2021-09-15
- 期刊:
- 影响因子:5.6
- 作者:Lua J;Ekanayake K;Fangman M;Doré S
- 通讯作者:Doré S
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Sylvain DORE其他文献
Sylvain DORE的其他文献
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{{ truncateString('Sylvain DORE', 18)}}的其他基金
Potential stroke therapeutic efficacy of FumET-CORM through the Nrf2 pathway
FumET-CORM 通过 Nrf2 通路的潜在中风治疗功效
- 批准号:
9751526 - 财政年份:2019
- 资助金额:
$ 38.13万 - 项目类别:
Regulation and Implication of Hemoglobin Clearance in Subarachnoid Hemorrhagic Patients
蛛网膜下腔出血患者血红蛋白清除率的调节及意义
- 批准号:
9332485 - 财政年份:2016
- 资助金额:
$ 38.13万 - 项目类别:
Regulation and Implication of Hemoglobin Clearance in Subarachnoid Hemorrhagic Patients
蛛网膜下腔出血患者血红蛋白清除率的调节及意义
- 批准号:
9182501 - 财政年份:2016
- 资助金额:
$ 38.13万 - 项目类别:
Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok
更好地了解高丽参对中风的神经保护机制
- 批准号:
9128625 - 财政年份:2012
- 资助金额:
$ 38.13万 - 项目类别:
Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok
更好地了解高丽参对中风的神经保护机制
- 批准号:
8708765 - 财政年份:2012
- 资助金额:
$ 38.13万 - 项目类别:
Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok
更好地了解高丽参对中风的神经保护机制
- 批准号:
8369356 - 财政年份:2012
- 资助金额:
$ 38.13万 - 项目类别:
Better Understanding of the Neuroprotective Mechanisms of Korean Ginseng in Strok
更好地了解高丽参对中风的神经保护机制
- 批准号:
8543642 - 财政年份:2012
- 资助金额:
$ 38.13万 - 项目类别:
Effect of Flavanol-Rich Cocoa Extract in Acute Neurodegenerative Conditions
富含黄烷醇的可可提取物对急性神经退行性疾病的作用
- 批准号:
8117138 - 财政年份:2010
- 资助金额:
$ 38.13万 - 项目类别:
Effect of Flavanol-Rich Cocoa Extract in Acute Neurodegenerative Conditions
富含黄烷醇的可可提取物对急性神经退行性疾病的作用
- 批准号:
7989678 - 财政年份:2010
- 资助金额:
$ 38.13万 - 项目类别:
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