A Targeted Approach to Managing Salivary Gland Inflammation Using Resolvins
使用 Resolvins 治疗唾液腺炎症的有针对性的方法
基本信息
- 批准号:10386917
- 负责人:
- 金额:$ 36.8万
- 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:2020-08-10 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAreaAspirinAutoantibodiesAutoimmune DiseasesBiopsyBloodBlood CirculationCD59 AntigenCell Culture TechniquesCell SurvivalCellsChronicCoupledCytokine SignalingDestinationsDevelopmentDiagnosticDiffuseDiffusionDiseaseDopamine D1 ReceptorDoseDrynessEicosanoidsFPR2 geneFaceFamilyFunctional disorderFutureGTP-Binding ProteinsGoalsHalf-LifeHumanInfectionInfiltrationInflammationInflammatoryInjuryInvestigationKnock-in MouseKnockout MiceLeadLightLipidsLymphocyteMediatingMediator of activation proteinMethodsMinor salivary gland structureMusOral cavityOral healthOxidoreductasePathway interactionsPatientsPharmaceutical PreparationsPlasmaProcessProductionPropertyQuality of lifeRecoveryRecurrenceResolutionSalivaSalivarySalivary GlandsSalivary duct structureSialadenitisSignal PathwaySignal TransductionSjogren&aposs SyndromeStreamSubmandibular glandSystemTherapeuticTimeTissuesTranslatingWomanXerostomiabaseclinical applicationcytokineeffective therapyhuman diseaseimprovedmouse modelnoveloptimal treatmentspreservationreceptorresponsesaliva secretionsalivary celltargeted deliverytranslational study
项目摘要
ABSTRACT
Sjögren's syndrome (SS) is an autoimmune disease characterized by chronic inflammation and diminished
secretory function of the salivary glands (SG). Diagnostic features include dry mouth, lymphocytic infiltration
into the SG and presence of antinuclear autoantibodies in plasma. SS greatly decreases the patient’s quality of
life, and although extensive investigation has been done to understand it, causes of and effective treatments
for the disease are still unknown. In light of the high degree of need and the limitations of current therapies,
development of novel treatments to decrease inflammation and restore SG secretory function is essential. Our
previous studies demonstrated that SG express the AT-RvD1 receptor ALX/FPR2 to block pro-inflammatory
cytokine signaling, thereby promoting cell survival and tissue integrity in SS. More recently, we demonstrated
that AT-RvD1 treatment in SS-like NOD/ShiLtJ mice fully preserves secretory functioning, downregulates pro-
inflammatory cytokine expression and promotes pro-resolving signaling pathways. Encouraging as these
results may be, however, lymphocytic infiltration persists in AT-RvD1 treated SS mice, raising the possibility of
future pro-inflammatory cytokine production and possible recurrence of hypofunction. Moreover, we face
issues related to the properties of resolvins themselves that must be overcome for clinical applications to be
achieved. Specifically, a significant portion of administered resolvins (RvD1 included) do not reach their
intended destination with the desired regularity because they are quickly inactivated by eicosanoid
oxidoreductases (EOR) and their effects can be diffusely distributed throughout the body. Furthermore, the
problem of instability extends to the AT forms, which are somewhat less susceptible to inactivation. In addition
to these issues of durability, resolvins are relatively expensive, and when taken together, these concerns raise
questions about the feasibility of any treatment requiring large doses to be introduced into the blood stream. In
response, we believe that all of these issues may be addressed by infusing AT-RvD1 retrograde to the salivary
ducts, which could allow the benefits demonstrated by AT-RvD1 (i.e., preserved and/or restored saliva
secretion) to be retained while addressing areas of weakness discussed earlier. Moreover, to better exploit the
use of AT-RvD1, we will study the mechanisms by which it activates the ALX/FPR2 using a knock-out mouse
for this receptor (ALX/FPR2-/-). Next, we will describe the ALX/FPR2 signaling mechanisms in mouse and
human cells. Finally, we will determine whether ALX/FPR2 signaling pathways are altered in minor SG
biopsies (both with and without SS), thereby further extending our findings to the human disease. Our overall
hypothesis is that healthy SG functioning will be restored by local AT-RvD1 treatment. Aim 1 will demonstrate
the benefits of delivering AT-RvD1 locally for restoring SG function. Aim 2 will determine ALX/FPR2 signaling
mechanisms and Aim 3 will translate ALX/FPR2 signaling mechanisms to humans.
抽象的
干燥综合征(SS)是一种自身免疫性疾病,其特征是慢性炎症和功能减退。
唾液腺的分泌功能(SG)的诊断特征包括口干、淋巴细胞浸润。
进入 SG 和血浆中存在抗核自身抗体会大大降低患者的治疗质量。
尽管已经进行了广泛的调查来了解它,但其原因和有效的治疗方法
鉴于这种疾病的高度需求和当前疗法的局限性,
开发减少炎症和恢复 SG 分泌功能的新疗法至关重要。
先前的研究表明,SG 表达 AT-RvD1 受体 ALX/FPR2 来阻断促炎细胞因子
最近,我们证明了细胞因子信号传导,从而促进 SS 中的细胞存活和组织完整性。
SS 样 NOD/ShiLtJ 小鼠中的 AT-RvD1 治疗完全保留了分泌功能,下调了促-
炎症细胞因子的表达并促进促消退信号通路,这些令人鼓舞。
然而,结果可能是,AT-RvD1 治疗的 SS 小鼠中淋巴细胞浸润持续存在,这增加了以下可能性:
未来促炎细胞因子的产生和可能的功能减退复发。
与分解素本身特性相关的问题必须克服才能临床应用
具体来说,很大一部分施用的解决方案(包括 RvD1)未达到其目标。
具有所需规律性的预期目的地,因为它们很快就会被类二十烷酸灭活
氧化还原酶(EOR)及其作用可广泛分布于全身。
不稳定的问题也延伸到了 AT 形式,它们不太容易失活。
对于这些耐久性问题,解决方案相对昂贵,综合考虑,这些问题引起了人们的关注
关于任何需要将大剂量引入血流的治疗的可行性的问题。
响应,我们相信所有这些问题都可以通过将 AT-RvD1 逆行注入唾液来解决
导管,这可以让 AT-RvD1 所展示的好处(即保存和/或恢复唾液
分泌)被保留,同时解决前面讨论的弱点领域,此外,为了更好地利用
使用 AT-RvD1,我们将使用敲除小鼠研究它激活 ALX/FPR2 的机制
接下来,我们将描述小鼠中的 ALX/FPR2 信号传导机制。
最后,我们将确定 ALX/FPR2 信号通路在轻微 SG 中是否发生改变。
活检(有和没有 SS),从而进一步将我们的发现扩展到人类疾病的整体。
假设目标 1 将证明局部 AT-RvD1 治疗将恢复健康的 SG 功能。
本地传送 AT-RvD1 恢复 SG 功能的好处将决定 ALX/FPR2 信令。
机制和 Aim 3 将把 ALX/FPR2 信号机制转化为人类。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Specialized pro-resolving receptors are expressed in salivary glands with Sjögren's syndrome.
- DOI:10.1016/j.anndiagpath.2021.151865
- 发表时间:2022-03
- 期刊:
- 影响因子:2
- 作者:Dos Santos HT;Nam K;Maslow F;Trump B;Baker OJ
- 通讯作者:Baker OJ
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Olga Juliana Baker其他文献
Olga Juliana Baker的其他文献
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{{ truncateString('Olga Juliana Baker', 18)}}的其他基金
2023 Salivary Glands and Exocrine Biology GRC and GRS
2023年唾液腺和外分泌生物学GRC和GRS
- 批准号:
10598716 - 财政年份:2023
- 资助金额:
$ 36.8万 - 项目类别:
A Targeted Approach to Managing Salivary Gland Inflammation Using Resolvins
使用 Resolvins 治疗唾液腺炎症的有针对性的方法
- 批准号:
10250559 - 财政年份:2020
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
8296970 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
8922199 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
8831636 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
RESOLUTION OF CYTOKINE-MEDIATED SALIVARY GLAND INFLAMMATION
细胞因子介导的唾液腺炎症的解决
- 批准号:
9507142 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
8460463 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
8930244 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
9098091 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
Resolution of Cytokine-Mediated Salivary Gland Inflammation
细胞因子介导的唾液腺炎症的解决
- 批准号:
8656973 - 财政年份:2012
- 资助金额:
$ 36.8万 - 项目类别:
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