Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
基本信息
- 批准号:10609870
- 负责人:
- 金额:$ 49.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-04-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:6 year oldAdipocytesAdrenergic AntagonistsBenignBindingBlood VesselsBreathingCell SeparationCellsChildChromatinChromosomal translocationCopy Number PolymorphismCorneal NeovascularizationDataDeformityDidelphidaeDimerizationDominant-Negative MutationEndothelial CellsEndotheliumFaceFundingGene FusionGenesGeneticGenetic TranscriptionGoalsGrowthHemangioendotheliomaHemangiomaHomeHomoHumanHypotrichosisImmuneImplantIn VitroInfantKidneyLearningLife Cycle StagesLocationLymphedemaMedicalMethodsModelingMolecularMusMutationNeoplasms in Vascular TissueNuclear ExtractNude MiceOperative Surgical ProceduresOrganPathogenesisPathologicPathway interactionsPatientsPericytesPharmaceutical PreparationsPrevalenceProgress ReportsPropranololPublicationsReagentRoleSOX18 geneSamplingSomatic MutationSpecimenStrawberry nevusStructureSyndromeTelangiectasisTestingTimeTissuesTranscriptVariantVascular DiseasesVascular ProliferationVisual impairmentWorkXenograft Modelbeta-adrenergic receptorbioinformatics toolblood vessel developmentdimereffective therapyenantiomerendothelial stem cellexomeexperimental studyfeedinggenome sequencinghuman stem cellsimprovedin vivo Modelinfancyinsightknock-downneovascularneovascularizationnext generation sequencingnovelpharmacologicpreventsmall hairpin RNAsmall molecule inhibitorstem cellstranscription factortranscriptome sequencingwhole genome
项目摘要
Project Abstract
Infantile hemangioma (IH) is a common vascular tumor with a unique lifecycle of rapid blood vessel formation
over the first 6-9 months of infancy, followed by a slow spontaneous involution of blood vessels over several
years. For most children, IH does not pose a serious threat and therapy is unnecessary; however, in about
10% of cases, IH can enlarge dramatically, threaten organs and cause permanent disfigurement. Over the last
10 years, propranolol, a well-known non-selective β-adrenergic receptor antagonist, has emerged as first-line
therapy for endangering IH, yet how and why it works so well in reducing the vascular overgrowth in IH has
remained a mystery. There is a significant need to improve propranolol therapy because up to 18% of IHs fail
to respond, up to 25% resume growth when the drug is stopped, and 37% of propranolol-treated infants require
surgery at 5-6 years of age to minimize deformity caused by remaining fibrofatty residua. To improve on
propranolol, it is essential to elucidate it’s mechanism of action against vascular overgrowth, which will then
provide a path forward to advance IH medical therapy, and potentially other neovascular diseases as well.
In previous funding cycles, we identified a hemangioma stem cell (HemSC) from human IH surgical specimens
that can differentiate into endothelial cells, pericytes and adipocytes and form hemangioma-like vessels within
7 days when implanted into immune-deficient mice. Subsequent studies from our lab and others validate
HemSCs as the IH-initiating cell. Our recent results show that a small molecule inhibitor of the transcription
factor SOX18 and propranolol both effectively block HemSC-to-endothelial differentiation. Furthermore, the
R(+) enantiomer of propranolol, which lacks β-adrenergic receptor antagonistic activity, is equally effective.
This novel discovery identifies a β-adrenergic receptor-independent, SOX18-dependent mechanism by which
propranolol reduces vascular overgrowth in IH. To investigate deeply, we propose three specific aims. Aim 1
will directly and rigorously test the requirement for SOX18 in IH vessel formation using our in vivo model in
which IH-derived HemSC form IH-like blood vessels in nude mice. Aim 2 will investigate dimerization status of
SOX18 in IH (sub-aim 2a), how propranolol and the R(+) enantiomer disrupt SOX18 dimerization and sub-
cellular localization (sub-aim 2b), and how this alters transcription to prevent HemSC-blood vessel formation
(sub-aim 2c). Aim 3, conducted in parallel, will analyze our existing next generation sequencing data using
new bioinformatic tools to identify potential chromosomal translocations or small copy number variants that
could produce fusion transcripts with new activities (sub-aim 3a) and will perform deep coverage RNA-Seq on
IH tissue and freshly isolated IH cells as an alternative method to identify fusion transcripts (sub-aim 3b); once
identified, the connection to SOX18 and IH vessel formation will tested in in vitro and in vivo models.
项目摘要
项目成果
期刊论文数量(30)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Endoglin regulates mural cell adhesion in the circulatory system.
- DOI:10.1007/s00018-015-2099-4
- 发表时间:2016-04
- 期刊:
- 影响因子:0
- 作者:Rossi E;Smadja DM;Boscolo E;Langa C;Arevalo MA;Pericacho M;Gamella-Pozuelo L;Kauskot A;Botella LM;Gaussem P;Bischoff J;Lopez-Novoa JM;Bernabeu C
- 通讯作者:Bernabeu C
IGF-2 and FLT-1/VEGF-R1 mRNA levels reveal distinctions and similarities between congenital and common infantile hemangioma.
IGF-2 和 FLT-1/VEGF-R1 mRNA 水平揭示了先天性血管瘤和普通婴儿血管瘤之间的区别和相似之处。
- DOI:10.1203/pdr.0b013e318163a243
- 发表时间:2008
- 期刊:
- 影响因子:3.6
- 作者:Picard,Arnaud;Boscolo,Elisa;Khan,ZiaA;Bartch,TatiannaC;Mulliken,JohnB;Vazquez,MariePaule;Bischoff,Joyce
- 通讯作者:Bischoff,Joyce
Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells.
- DOI:10.1002/stem.1841
- 发表时间:2015-01
- 期刊:
- 影响因子:5.2
- 作者:Huang, Lan;Nakayama, Hironao;Klagsbrun, Michael;Mulliken, John B.;Bischoff, Joyce
- 通讯作者:Bischoff, Joyce
Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma.
- DOI:10.1038/jid.2011.300
- 发表时间:2011-12
- 期刊:
- 影响因子:6.5
- 作者:Greenberger, Shoshana;Yuan, Siming;Walsh, Logan A.;Boscolo, Elisa;Kang, Kyu-Tae;Matthews, Benjamin;Mulliken, John B.;Bischoff, Joyce
- 通讯作者:Bischoff, Joyce
α6-Integrin is required for the adhesion and vasculogenic potential of hemangioma stem cells.
血管瘤干细胞的粘附和血管生成潜力需要α6-整合素。
- DOI:10.1002/stem.1539
- 发表时间:2014-03
- 期刊:
- 影响因子:5.2
- 作者:Smadja, David M.;Guerin, Coralie L.;Boscolo, Elisa;Bieche, Ivan;Mulliken, John B.;Bischoff, Joyce
- 通讯作者:Bischoff, Joyce
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Joyce E. Bischoff其他文献
Joyce E. Bischoff的其他文献
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{{ truncateString('Joyce E. Bischoff', 18)}}的其他基金
Pediatric Surgeon-Scientist Training Program in Vascular Diseases
小儿外科医生-科学家血管疾病培训计划
- 批准号:
10331916 - 财政年份:2022
- 资助金额:
$ 49.42万 - 项目类别:
Pediatric Surgeon-Scientist Training Program in Vascular Diseases
小儿外科医生-科学家血管疾病培训计划
- 批准号:
10619547 - 财政年份:2022
- 资助金额:
$ 49.42万 - 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
- 批准号:
10206231 - 财政年份:2016
- 资助金额:
$ 49.42万 - 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
- 批准号:
10630310 - 财政年份:2016
- 资助金额:
$ 49.42万 - 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
- 批准号:
10058384 - 财政年份:2016
- 资助金额:
$ 49.42万 - 项目类别:
Capillary malformation: From somatic GNAQ mutations to disrupted endothelial biology
毛细血管畸形:从体细胞 GNAQ 突变到内皮生物学破坏
- 批准号:
10414083 - 财政年份:2016
- 资助金额:
$ 49.42万 - 项目类别:
Capillary malformation: From somatic GNAQ mutations and disrupted endothelial biology
毛细血管畸形:来自体细胞 GNAQ 突变和内皮生物学破坏
- 批准号:
9244833 - 财政年份:2016
- 资助金额:
$ 49.42万 - 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
- 批准号:
8248244 - 财政年份:2009
- 资助金额:
$ 49.42万 - 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
- 批准号:
9973341 - 财政年份:2009
- 资助金额:
$ 49.42万 - 项目类别:
Blood vessel assembly from multipotent hemangioma-derived stem cells
来自多能血管瘤干细胞的血管组装
- 批准号:
7789467 - 财政年份:2009
- 资助金额:
$ 49.42万 - 项目类别:
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