Identification of eye-homing peptides and their use for targeted liposomal drug delivery in posterior uveitis
眼归巢肽的鉴定及其在后葡萄膜炎靶向脂质体药物递送中的应用
基本信息
- 批准号:10612913
- 负责人:
- 金额:$ 19.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdjuvant ArthritisAdverse effectsAffectAlzheimer&aposs DiseaseAmino AcidsAnimal Cancer ModelAnimalsAntibodiesAntigensArthritisAttentionAutoantigensAutoimmuneAutoimmune DiseasesAutoimmunityBacteriophagesBindingBiological AvailabilityBiologyBlindnessBlood VesselsBlood-Retinal BarrierCellsCharacteristicsChoroidChronic DiseaseCollaborationsCyclic PeptidesCysteineDiseaseDrug Delivery SystemsDrug TargetingEncapsulatedEndotheliumExperimental Autoimmune EncephalomyelitisEyeEye diseasesGene Expression ProfilingHemorrhageHeterogeneityHomeHomingHumanHypoxiaImmuneImmunizationIndividualInflammationInflammation MediatorsJointsLesionLibrariesLigandsLiposomesLymphoid TissueMediatorMethodologyMethodsMethotrexateModelingMolecularMolecular ProfilingMultiple SclerosisNeural RetinaOrganOxygenPathogenesisPathogenicityPathologyPeptide LibraryPeptide Phage Display LibraryPeptidesPeripheralPharmaceutical PreparationsPharmacodynamicsPosterior UveitisProceduresProcessProteinsPublishingRattusReportingRetinaRetinal DetachmentRetinal DiseasesRheumatoid ArthritisRodentSiteSpecificityT-LymphocyteTestingTissuesTopical applicationToxic effectUveaUveitisVascular EndotheliumVisual impairmentWorkanterior chamberautoimmune pathogenesisautoimmune uveitisautoreactive T celldesignhuman modelimprovedin vivoinnovationinterstitial retinol-binding proteinintravitreal injectionmedication safetymigrationmolecular markernanoparticleneoplastic cellnovelnovel therapeuticsposterior eyeball chamberprotein aminoacid sequencescreeningsystemic toxicitytooltraffickingtumor
项目摘要
Human posterior segment uveitis of autoimmune origin is a chronic disease that can impair vision and
result in blindness. A variety of autoantigens, including interphotoreceptor retinoid binding protein (IRBP), have
been implicated in uveitis pathogenesis. The T cells reactive against these antigens access the eye through
the blood-retinal barrier and cause local inflammation and tissue damage. Two of the main challenges in non-
infectious posterior uveitis are – 1) to define the molecular changes induced during uveitis in endothelium of
the choroidal and retinal vasculature, and 2) to devise novel ways to direct the systemically-administered drugs
primarily into the eye to enhance their efficacy but minimize adverse effects. We hypothesize that the vascular
endothelium of the eye in uveitis is characterized by unique molecular markers that facilitate both selective
migration of the pathogenic T cells into the target organ and cellular interaction with the inducers/ mediators of
inflammation and tissue damage. Accordingly, the identification of peptide ligands (by phage peptide library
screening) that interact with such markers would be invaluable tools to study disease pathogenesis.
Furthermore, these peptide ligands can be exploited for targeted drug delivery to the eye with the objective of
enhancing efficacy, but reducing systemic toxicity of those drugs. In collaboration with Dr. Erkki Ruoslahti
(Sanford-Burnham, La Jolla), who pioneered the concept of vascular ‘address molecules’ or ‘zip codes’, we
published a study on the molecular profiling of the synovial vasculature in adjuvant arthritis in rats (PNAS
2011). We identified unique joint-homing peptide ligands using an innovative approach of ex vivo/ in vivo
enrichment of clones from a phage peptide-display library. Recently, we also reported CNS-homing peptides in
the EAE model of human multiple sclerosis. The advantage of using phages to detect tissue-specific markers
is that there is no a priori bias in predicting the peptide sequences/motifs. And, unlike antibodies, phage
peptides interact with functional domains of target molecules. We now plan to apply this methodology to rat
experimental autoimmune uveitis (EAU). The aims of our study in collaboration with experts in EAU (Dr. Caspi
and Dr. Sun), [in vascular biology (Dr. Teesalu from Ruoslahti group), and in pharmacodynamics (Dr. Swaan)]
are: Aim 1. To identify peptide ligands homing to the diseased eye in EAU using the ex vivo/ in vivo
screening of phage peptide library. (a) To identify unique peptide-encoding phages that home to the
vasculature and retina of the diseased eye; and (b) to determine the relative specificity of select phages/
peptides [for other tissues within the eye as well as other organs in EAU versus control (healthy/EAE) rats.]
Aim 2. To use the eye-homing peptides for targeted drug delivery to the diseased sites in EAU. To use
a specific peptide to guide liposomes encapsulating a drug (e.g., methotrexate) [to the diseased sites in eyes in
EAU, and compare the pharmacodynamics and safety of that drug] with that using plain liposomes or free drug.
The results would advance understanding of pathogenesis of human uveitis and designing of novel therapies.
自身免疫性起源的人后段葡萄膜炎是一种慢性疾病,
导致失明。多种自身抗原,包括光感受器间类维生素A结合蛋白(IRBP),
与葡萄膜炎发病机制有关。对这些抗原有反应的T细胞通过以下途径进入眼睛:
血视网膜屏障,并导致局部炎症和组织损伤。两个主要的挑战,在非
感染性后葡萄膜炎是:1)定义葡萄膜炎期间在内皮细胞中诱导的分子变化,
脉络膜和视网膜血管系统,以及2)设计新的方法来引导全身给药的药物
主要是进入眼睛,以提高其功效,但最大限度地减少副作用。我们假设血管
葡萄膜炎中的眼内皮的特征在于独特的分子标记物,
病原性T细胞向靶器官的迁移以及与病原性T细胞的诱导物/介导物的细胞相互作用
炎症和组织损伤。因此,肽配体的鉴定(通过噬菌体肽库
筛选)与这些标志物相互作用的基因将是研究疾病发病机制的宝贵工具。
此外,这些肽配体可用于向眼睛的靶向药物递送,目的是
增强功效,但降低这些药物的全身毒性。与Erkki Ruoslahti博士合作
(Sanford-Burnham,拉霍亚)是血管“地址分子”或“邮编”概念的先驱,我们
发表了一项关于大鼠佐剂性关节炎滑液血管系统分子谱的研究(PNAS
2011年)。我们使用体外/体内的创新方法鉴定了独特的联合归巢肽配体
从噬菌体肽展示文库富集克隆。最近,我们还报道了CNS归巢肽在
人类多发性硬化症的EAE模型。利用PCR检测组织特异性标志物的优势
在预测肽序列/基序时不存在先验偏差。与抗体不同,噬菌体
肽与靶分子的功能结构域相互作用。我们现在计划将这种方法应用于大鼠
实验性自身免疫性葡萄膜炎(EAU)。我们与EAU专家(Caspi博士)合作研究的目的是
和Sun博士),[血管生物学(Ruoslahti组的Teesalu博士)和药效学(Swaan博士)]
目标:1。使用离体/体内免疫荧光技术鉴定EAU中归巢至患病眼的肽配体,
噬菌体肽库的筛选。(a)为了鉴定独特的肽编码序列,
(B)确定所选血管和视网膜的相对特异性,
肽[EAU与对照(健康/EAE)大鼠眼内其他组织以及其他器官。]
目标2.目的利用眼归巢肽靶向治疗EAU。使用
引导包封药物的脂质体的特异性肽(例如,甲氨蝶呤)[在眼睛的患病部位,
EAU,并比较该药物与普通脂质体或游离药物的药效学和安全性。
本研究结果有助于加深对葡萄膜炎发病机制的认识和设计新的治疗方法。
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 }}
KAMAL D MOUDGIL其他文献
KAMAL D MOUDGIL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 }}
{{ truncateString('KAMAL D MOUDGIL', 18)}}的其他基金
Validation of the joint-homing and drug delivery attributes of novel peptides in a mouse arthritis model
在小鼠关节炎模型中验证新型肽的关节归巢和药物递送特性
- 批准号:
10589192 - 财政年份:2023
- 资助金额:
$ 19.31万 - 项目类别:
Identification of eye-homing peptides and their use for targeted liposomal drug delivery in posterior uveitis
眼归巢肽的鉴定及其在后葡萄膜炎靶向脂质体药物递送中的应用
- 批准号:
10452321 - 财政年份:2022
- 资助金额:
$ 19.31万 - 项目类别:
Anti-arthritic activity and therapeutic use of novel joint-homing peptides
新型关节归巢肽的抗关节炎活性和治疗用途
- 批准号:
8998611 - 财政年份:2015
- 资助金额:
$ 19.31万 - 项目类别:
Anti-arthritic activity and therapeutic use of novel joint-homing peptides
新型关节归巢肽的抗关节炎活性和治疗用途
- 批准号:
9339552 - 财政年份:2015
- 资助金额:
$ 19.31万 - 项目类别:
Identification of CNS-homing peptides for therapeutic use in multiple sclerosis
鉴定用于治疗多发性硬化症的中枢神经系统归巢肽
- 批准号:
8897016 - 财政年份:2013
- 资助金额:
$ 19.31万 - 项目类别:
Identification of CNS-homing peptides for therapeutic use in multiple sclerosis
鉴定用于治疗多发性硬化症的中枢神经系统归巢肽
- 批准号:
8638421 - 财政年份:2013
- 资助金额:
$ 19.31万 - 项目类别:
Defining glomerulus-homing peptides for targeted drug delivery in lupus nephritis
定义用于狼疮性肾炎靶向药物递送的肾小球归巢肽
- 批准号:
8787075 - 财政年份:2013
- 资助金额:
$ 19.31万 - 项目类别:
Immune Modulation of Autoimmunity by Herbal Products
草药产品对自身免疫的免疫调节
- 批准号:
8290064 - 财政年份:2009
- 资助金额:
$ 19.31万 - 项目类别:
Immune Modulation of Autoimmunity by Herbal Products
草药产品对自身免疫的免疫调节
- 批准号:
8103241 - 财政年份:2009
- 资助金额:
$ 19.31万 - 项目类别:
Immune Modulation of Autoimmunity by Herbal Products
草药产品对自身免疫的免疫调节
- 批准号:
7898955 - 财政年份:2009
- 资助金额:
$ 19.31万 - 项目类别:
相似海外基金
Glutamine, dietary fiber, oligosaccharide and Bifidobacterium lungum exert symbiotic effects on adjuvant arthritis in rats.
谷氨酰胺、膳食纤维、低聚糖和肺双歧杆菌对大鼠佐剂性关节炎发挥共生作用。
- 批准号:
26350157 - 财政年份:2014
- 资助金额:
$ 19.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
EFFECT OF AUTOREACTIVE CELL LINES ON ADJUVANT ARTHRITIS
自身反应细胞系对佐剂性关节炎的影响
- 批准号:
3952965 - 财政年份:
- 资助金额:
$ 19.31万 - 项目类别: