Semaphorin3d and anomalous pulmonary venous return

Semaphorin3d 和异常肺静脉回流

• 批准号: 9108432
• 负责人: Jonathan A. Epstein
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108432
• 关键词: Address; Affect; Alleles; Animal Model; Area; Axon; Binding; Blood; Blood Vessels; Books; Candidate Disease Gene; Cardiac; Cardiovascular system; Cells; Chick Embryo; Complex; Congenital Heart Defects; Cues; Data; Development; Disease; Endothelial Cells; Endothelium; Epicardium; Funding; Genetic; Growth; Health; Heart; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Left; Link; Lung; Malignant Neoplasms; Mediating; Modeling; Mus; Mutation; Neuropilins; Patients; Pattern; Pregnancy; Principal Investigator; Pulmonary veins; Role; Semaphorins; Shunt Device; Signal Pathway; Signal Transduction; Testing; Text; Textbooks; Therapeutic Agents; United States National Institutes of Health; VEGFA gene; Veins; Venous; Work; Zebrafish; angiogenesis; congenital heart disorder; in vivo; knock-down; migration; mutant; notch protein; plexin; prevent; programs; rare variant; receptor; small hairpin RNA

DESCRIPTION (provided by applicant): Anomalous pulmonary venous return is a common form of congenital heart disease though little is known about how the pulmonary veins are normally patterned. Semaphorins are guidance molecules that mediate repulsive cues for axons and blood vessels. We have generated two distinct null alleles of a poorly studied class III semaphorin, sema3d, which results in anomalous pulmonary venous return. Our data suggests that sema3d normally functions as a boundary, constraining migration of nascent pulmonary venous endothelium. The absence of sema3d allows for ectopic migration and patterning of pulmonary venous endothelial cells, leading to anomalous connections. These findings provide an altogether new description of the developmental cause of anomalous pulmonary veins that demands revision of common textbook explanations. In this proposal, we will test the hypothesis that sema3d binds directly to pulmonary venous endothelial cells causing repulsion. We will identify the functional sema3d receptor and the intracellular signaling pathways that result in repulsion, and we will examine how sema3d functionally interacts with Notch and Vegf during angiogenesis.

描述（由申请人提供）：异常的肺静脉回流是先天性心脏病的一种常见形式，尽管对通常如何对肺静脉的图案方式知之甚少。信号素是指导分子，可介导轴突和血管的排斥线索。我们已经产生了一个研究不足的III类词素SEMA3D的两个不同的无效等位基因，这导致异常的肺静脉回流。我们的数据表明，SEMA3D通常充当边界，限制了新生肺静脉内皮的迁移。 SEMA3D的不存在允许肺静脉内皮细胞的异位迁移和模式，从而导致异常连接。这些发现为需要修改常见教科书解释的异常肺静脉的发育原因提供了一个新的描述。在此提案中，我们将测试SEMA3D直接与引起排斥的肺静脉内皮细胞结合的假设。我们将确定功能性SEMA3D受体以及导致排斥的细胞内信号传导途径，我们将检查SEMA3D在血管生成过程中如何与Notch和VEGF功能相互作用。

项目成果

Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development.

• DOI: 10.1016/j.celrep.2016.04.027
• 发表时间: 2016-05-17
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Singh A;Ramesh S;Cibi DM;Yun LS;Li J;Li L;Manderfield LJ;Olson EN;Epstein JA;Singh MK
• 通讯作者: Singh MK

Genetic dissection of plexin signaling in vivo

体内丛蛋白信号传导的基因剖析

• DOI: 10.1073/pnas.1308418111
• 发表时间: 2014
• 期刊: Proc Natl Acad Sci USA
• 作者: Worzfeld T;Swiercz JM;Senturk A;Genz B;Korostylev A;Deng S;Xia J;Hoshino M;Epstein JA;Chan AM;Vollmar B;Acker-Palmer A;Kuner R;Offermanns S
• 通讯作者: Offermanns S

Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor.

• DOI: 10.1038/ncomms12038
• 发表时间: 2016-06-30
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Aghajanian H;Cho YK;Manderfield LJ;Herling MR;Gupta M;Ho VC;Li L;Degenhardt K;Aharonov A;Tzahor E;Epstein JA
• 通讯作者: Epstein JA