Novel lymphatic genes that regulate heart valve development and disease
调节心脏瓣膜发育和疾病的新型淋巴基因
基本信息
- 批准号:10585707
- 负责人:
- 金额:$ 56.27万
- 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:2022-12-15 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:ADAMTSAnabolismBiochemicalBlood VesselsBlood flowCardiacCardiovascular systemCharacteristicsCollagenDataDefectDevelopmentDiseaseDoxycyclineElastinEndothelial CellsEndotheliumEtiologyExtracellular MatrixExtracellular Matrix ProteinsFOXC2 geneGenesGrowthHeartHeart Valve DiseasesHeart ValvesHomeoboxIn VitroIndividualInflammationLightLymphLymphaticLymphedemaMaintenanceMitral ValveModelingMolecularMusOutcomePathway interactionsPeptide HydrolasesPharmaceutical PreparationsPhenocopyPhenotypePhysiologicalPlatelet-Derived Growth FactorProductionProteoglycanPublic HealthResearchRoleSTAT1 geneSideSignal PathwaySignal TransductionStructureSyndromeTestingTherapeuticThinnessVeinsVenousWorkaggrecanaortic valvecell typeexperiencegain of functiongenetic approachhuman old age (65+)insightinterstitial cellloss of functionlymph flowlymphatic developmentlymphatic vesselmechanical forcemouse modelnoveloverexpressionpharmacologicpreventrare genetic disorderresponse to injurysmall hairpin RNAtranscription factorversican
项目摘要
PROJECT SUMMARY/ABSTRACT
Valves are present within hearts, veins and lymphatic vessels to regulate the flow of blood and lymph. Defects
in the development or functioning of valves could lead to diseases such as lymphedema and degenerative heart
valve disease. Venous and lymphatic (vascular) valves are composed of two layers of endothelial cells with a
thin layer of collagen-rich extra cellular matrix (ECM). Few if any interstitial cells are observed within vascular
valves. In contrast, cardiac valves are made of two major cell types: numerous ECM producing valvular interstitial
cells (VICs), which are surrounded by a single layer of valvular endothelial cells (VECs). Despite significant
differences in their structure and the mechanical force that they experience, cardiac and vascular valves share
interesting similarities. The homeobox transcription factor PROX1 is necessary for the development of vascular
valves. PROX1 is also expressed in a subset of VECs on the downstream side of heart valves. We have now
determined that the deletion of PROX1 from VECs results in the accumulation of proteoglycans and the
consequent thickening of heart valves. Thus, PROX1 in VECs regulates the development and functioning of
VICs through yet unknown mechanisms.
Building on our preliminary data we will test our Central Hypothesis that a previously unknown
PROX1àFOXC2àPDGF-B signaling pathway from downstream VECs regulates VIC identity and, in turn, the
ECM composition of valves.
Abnormally high synthesis of proteoglycans is observed in several valve disorders. Valve defects are
observed in ~8% in individuals >65 years old and ~13% in those who are >75. Pharmacological approaches to
treat these valve defects do not exist. Hence, the outcomes of our proposed research are expected to be
significant because they will substantially advance our insight into the molecular and cellular mechanisms of
VEC-VIC crosstalk during cardiac valve development and shed light on potential therapeutic strategies.
项目摘要/摘要
心脏、静脉和淋巴管内存在瓣膜,以调节血液和淋巴的流动。缺陷
瓣膜的发育或功能可能会导致淋巴水肿和心脏变性等疾病
瓣膜病。静脉瓣膜和淋巴(血管)瓣膜由两层内皮细胞组成,
薄层富含胶原的细胞外基质(ECM)。血管内观察到的间质细胞很少
阀门。相反,心脏瓣膜由两种主要细胞类型组成:大量细胞外基质产生瓣膜间质。
细胞(VIC),被单层瓣膜内皮细胞(VECs)包围。尽管意义重大
心脏瓣膜和血管瓣膜在结构和所受机械力上的不同是相同的。
有趣的相似之处。同源框转录因子PROX1在血管发育中的作用
阀门。PROX1也在心脏瓣膜下游的血管内皮细胞亚群中表达。我们现在有了
确定从血管内皮细胞中删除PROX1会导致蛋白多糖的积累和
随之而来的心脏瓣膜增厚。因此,血管内皮细胞中的PROX1调控血管内皮细胞的发育和功能。
受害者通过尚不清楚的机制。
基于我们的初步数据,我们将测试我们的中心假设,即以前未知的
来自下游血管内皮细胞的PROX1?FOXC2?PDGF-B信号通路调节血管内皮细胞的特性,进而调节血管内皮细胞的
阀门的ECM组成。
在几种瓣膜疾病中观察到蛋白多糖的异常高合成。阀门缺陷是
65岁的人和75岁的人分别有8%和13%的人出现这种情况。治疗的药理学方法
治疗这些阀门缺陷是不存在的。因此,我们建议的研究结果预计为
意义重大,因为它们将极大地促进我们对分子和细胞机制的了解
VEC-VIC在心脏瓣膜发育过程中的串扰,并阐明了潜在的治疗策略。
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)
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Rajanarayanan S Srinivasan其他文献
Rajanarayanan S Srinivasan的其他文献
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{{ truncateString('Rajanarayanan S Srinivasan', 18)}}的其他基金
Defining the Mechanisms of Lymphatic Vascular Growth and Function
定义淋巴血管生长和功能的机制
- 批准号:
10532232 - 财政年份:2016
- 资助金额:
$ 56.27万 - 项目类别:
Defining the Mechanisms of Lymphatic Vascular Growth and Function
定义淋巴血管生长和功能的机制
- 批准号:
10365381 - 财政年份:2016
- 资助金额:
$ 56.27万 - 项目类别:
Defining the mechanisms of lymphatic and lymphovenous valve development
定义淋巴管和淋巴静脉瓣发育的机制
- 批准号:
9194206 - 财政年份:2016
- 资助金额:
$ 56.27万 - 项目类别:
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