Pharmacologic modulation of innate immune dysfunction in heterotopic ossification
异位骨化中先天免疫功能障碍的药物调节
基本信息
- 批准号:9767025
- 负责人:
- 金额:$ 34.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:ACVR1 geneAcuteAffectAgonistAutoimmune DiseasesBiological AssayBone GrowthBone Morphogenetic ProteinsBypassCell physiologyCellsChemotaxisChondrogenesisChronicClinicalCoculture TechniquesDataDiseaseEndothelial CellsEndotheliumFlareFollow-Up StudiesFractureGeneticGenetic DiseasesGoalsHMGB1 geneHeterotopic OssificationHomeostasisHumanImatinibImmuneImmune Cell ActivationImmune System DiseasesImmune systemImmunologicsInflammationInflammatoryInflammatory ResponseInjuryInnate Immune SystemInterventionIntervention TrialKnowledgeLeadLesionLeukocytesLigandsLinkLipopolysaccharidesMutationNatural ImmunityOsteogenesisParentsPathway interactionsPatientsPeripheralPharmacologic SubstancePharmacologyPhasePhysiologic OssificationProductionPublic HealthRandomizedS100A8 geneS100A9 geneSeveritiesSignal TransductionSirolimusSkeletal DevelopmentT-LymphocyteTLR1 geneTLR2 geneTLR4 geneTestingTimeTraumaactivin Abonecell typecohortcytokinediagnostic biomarkereffective therapyefficacy studyimprovedinduced pluripotent stem cellinflammatory milieuinnate immune functionmacrophagemast cellmineralizationmonocytemouse modelnovelopen labelprogramsprogressive myositis ossificansreceptorrepairedresponseretinoic acid receptor gammatranscriptome sequencingtreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
Heterotopic ossification is a rare but devastating condition of inappropriate bone formation. Although immune
system activity is a critical contributor to heterotopic ossification, we lack a clear understanding of how the
immune system drives bone formation. Fibrodysplasia ossificans progressiva (FOP) is a genetic disease of
massive heterotopic ossification that is associated with inflammatory “flares” that can occur after injury. We
recently found that sera from FOP patients have increased levels of pro-inflammatory cytokines at baseline.
Furthermore, primary FOP monocytes showed increased responsiveness to LPS, a ligand that stimulates the
TLR4 pathway, but not to other ligands that activate other TLR receptors. These preliminary results lead to our
central hypothesis that FOP is an autoimmune disease caused by inappropriate activation of the innate
immune system. Although there are currently no effective treatments for FOP, retinoic acid receptor-γ (RAR-γ)
agonists can inhibit heterotopic ossification in mouse models. UCSF is part of an ongoing multicenter Phase II/III
program sponsored by Clementia Pharmaceuticals to study the efficacy of the RAR-γ agonist palovarotene in
blocking bone formation in FOP. Preliminary results from a completed randomized study (NCT02190747) and
ongoing open label followup study (NCT02279095) indicate that palovarotene can decrease the amount of
heterotopic bone formation in FOP subjects. The ongoing open label PVO-1A-202 (NCT02279095) and Phase
III PVO-1A-301 (NCT03312634) interventional trials will be the parent studies for the proposed unique
and time-sensitive opportunity to elucidate the immune mechanisms in FOP. In Aim 1, we will elucidate
how FOP primary monocytes respond to endogenous TLR4 activation. We will assay FOP sera for known
endogenous TLR4 activators that can be expressed after trauma, and test if FOP monocytes show increased
responsiveness to the TLR4 activators such as HMGB1. In Aim 2, we will test if FOP primary monocytes sensitize
endothelial cells to inflammation. We will use co-cultures to assay if FOP monocytes show increased chemotaxis
towards FOP endothelial cells and if this is dampened by palovarotene. We will also test if FOP endothelial cells
show enhanced pro-inflammatory cytokine expression in the presence of FOP monocytes. These assessments
will also show if palovarotene affects immune cell function. In Aim 3, we will determine how ACVR1 and
palovarotene change innate immune cell activation. We will use single cell RNAseq to elucidate how the ACVR1
R206H mutation changes the composition of peripheral immune cells, if palovarotene can normalize this profile,
and if changes in cytokine production can be linked to inflammation and FOP clinical heterotopic bone formation.
Our results will reveal critical inflammatory mechanisms that may provide the first mechanistic and
diagnostic biomarkers for disease activity in FOP. The results may also improve our treatment strategies
by identifying novel inflammatory targets that may be relevant to other conditions of heterotopic
ossification.
项目摘要/摘要
异位骨化是一种罕见但破坏性的不适当骨形成情况。虽然免疫
系统活动是异位骨化的关键因素,我们缺乏明确的了解
免疫系统驱动骨形成。进行性骨化性纤维发育不良(FOP)是一种遗传性疾病。
大量异位骨化,与损伤后可能发生的炎性“红斑”有关。我们
最近发现FOP患者的血清在基线水平上增加了促炎细胞因子的水平。
此外,原代FOP单核细胞对内毒素的反应性增强,内毒素是一种刺激血管内皮细胞生长的配体。
TLR4途径,而不是激活其他TLR受体的其他配体。这些初步结果导致了我们的
FOP是一种自身免疫性疾病的中心假设是由于先天不适当的激活引起的
免疫系统。尽管目前还没有有效的治疗方法,但维甲酸受体-γ(RAR-γ)
激动剂可以抑制小鼠模型的异位成骨。加州大学旧金山分校是正在进行的多中心II/III阶段的一部分
由铁线莲制药公司赞助的研究RAR-γ激动剂帕罗罗汀在
阻断FOP的骨形成。完成的随机研究的初步结果(NCT02190747)和
正在进行的开放标签随访研究(NCT02279095)表明,帕洛胡萝卜素可以减少
FOP受试者的异位骨形成。正在进行的开放标签PVO-1A-202(NCT02279095)和阶段
III PVO-1A-301(NCT03312634)介入试验将是提议的独一无二的亲代研究
和时间敏感的机会来阐明FOP的免疫机制。在目标1中,我们将阐明
FOP原代单核细胞对内源性TLR4激活的反应。我们将化验FOP血清以确定
创伤后可表达的内源性TLR4激活物,并检测FOP单核细胞是否表现为增加
对HMGB1等TLR4激活剂的反应性。在目标2中,我们将测试FOP原代单核细胞是否致敏
内皮细胞对炎症反应。我们将使用共培养来检测FOP单核细胞是否表现出更强的趋化性
对FOP内皮细胞的作用,如果这种作用被软脂素抑制的话。我们还将测试FOP内皮细胞
在FOP单核细胞存在的情况下,显示促炎症细胞因子的表达增强。这些评估
还将显示棕榈酸是否会影响免疫细胞功能。在目标3中,我们将确定ACVR1和
棕榈胡萝卜素改变先天免疫细胞的激活。我们将使用单细胞RNAseq来阐明ACVR1是如何
R206H突变改变了外周免疫细胞的组成,如果帕罗瓦罗汀能使这一图谱正常化,
如果细胞因子产生的变化可以与炎症和FOP临床异位骨形成联系起来。
我们的结果将揭示关键的炎症机制,可能提供第一个机制和
FOP中疾病活动性的诊断生物标志物。这一结果也可能改善我们的治疗策略。
通过识别可能与异位其他情况相关的新的炎症靶点
骨化。
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 }}
EDWARD C HSIAO其他文献
EDWARD C HSIAO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('EDWARD C HSIAO', 18)}}的其他基金
Novel Strategies for Understanding and Treating Fibrous Dysplasia
理解和治疗纤维发育不良的新策略
- 批准号:
10658595 - 财政年份:2023
- 资助金额:
$ 34.78万 - 项目类别:
the Gut Microbiome as a Disease Modifier of Heterotopic Ossification
肠道微生物组作为异位骨化的疾病调节剂
- 批准号:
10624949 - 财政年份:2022
- 资助金额:
$ 34.78万 - 项目类别:
Pharmacologic modulation of innate immune dysfunction in heterotopic ossification
异位骨化中先天免疫功能障碍的药物调节
- 批准号:
10196945 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
Innate immune regulation of stem cells in bone formation
干细胞在骨形成中的先天免疫调节
- 批准号:
9134038 - 财政年份:2015
- 资助金额:
$ 34.78万 - 项目类别:
Innate immune regulation of stem cells in bone formation
干细胞在骨形成中的先天免疫调节
- 批准号:
9341896 - 财政年份:2015
- 资助金额:
$ 34.78万 - 项目类别:
Innate immune regulation of stem cells in bone formation
干细胞在骨形成中的先天免疫调节
- 批准号:
9769508 - 财政年份:2015
- 资助金额:
$ 34.78万 - 项目类别:
相似海外基金
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 34.78万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 34.78万 - 项目类别:
Standard Grant