Snrk-1 and Dusp-5 co-ordinately regulate vascular development in vertebrates

Snrk-1 和 Dusp-5 协调调节脊椎动物的血管发育

基本信息

批准号：
8191883
负责人：
Ramani Ramchandran
金额：
$ 37.5万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8191883
关键词：
ACVRL1 gene Affect Angioblast Arteriovenous malformation Biology Birth Blood Vessels Cations Cells Cellular biology Classification Clinic Clinical Common Neoplasm Data Development Developmental Biology Disease Dysplasia Embryo Embryonic Development Endothelial Cells Environment Event FDA approved Family Genes Goals Grant Health Hemangioma Hereditary hemorrhagic telangiectasia Human In Vitro Inborn Genetic Diseases Individual Infant Lead Life Ligands Link Mission Mitogen-Activated Protein Kinases Molecular Molecular Biology Mucous Membrane Mutate Mutation Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Protein Dephosphorylation Protein-Serine-Threonine Kinases Public Health Research Role Signal Pathway Signal Transduction Signaling Molecule Skin Sucrose Testing Therapeutic Transforming Growth Factor Beta 2 Transforming Growth Factor beta Vertebrates Work base design drug development effective therapy human ROCK1 protein improved in vivo infancy innovation insight malformation member novel receptor response small molecule therapeutic target vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Vascular anomalies (VAs), inborn errors in embryonic vascular development are classified into two distinct groups: hemangiomas and vascular malformations (VMs). Current therapies for VAs are limited in efficacy and have significant complications. Therefore, to improve therapy for patients afflicted with these conditions, it is critical to identify the underlying mechanism leading to pathogenesis of VMs and hemangiomas. Our long-term goal is to understand the underlying mechanisms that lead to pathogenesis of VAs so that better therapeutics targeting this condition can be generated. In order to pursue that goal, the objective here is to study two recently identified genes by our group namely Sucrose non-fermenting receptor kinase-1 (Snrk-1), a serine- threonine kinase, and dual-specific phosphatase-5 (Dusp-5), a mitogen-activated protein kinase (MAPK) family, which are mutated in patients with hemangiomas and VMs. Our central hypothesis is that "transforming growth factor-beta (TGF-) ligand interacts with specific receptors (ALK-1/ALK-5) on endothelial cells transmitting signals via Snrk-1 and Dusp-5 to common substrate Rho-associated, coiled-coil containing protein kinase-1 (Rock-1) to induce specific responses in that cell and cells surrounding it." This hypothesis is formulated based on preliminary data from our group that identified several members (Alk-1, Alk-2, Smad-3, BMPR-2) of the TGF- signaling family and Rock-1 in a screen for substrates for Snrk-1. The rationale for the proposed research is that once it is determined how Snrk-1 and Dusp-5 modulate TGF- signaling in ECs and EC precursors (angioblasts) during embryonic development, we can target the TGF- Snrk-1/Dusp-5 signaling pathway with repurposed FDA-approved drugs thus providing better target based therapeutic options for VAs patients. The hypothesis will be tested by pursuing three specific aims: 1) Identify the contribution of cell autonomous vs. non-autonomous Snrk-1/Dusp-5 function and the role of Dusp-5 mutations in VA disease pathogenesis. 2) Identify the mechanistic role of Rock-1 in Snrk-1/Dusp-5 signaling in vivo and in vitro. 3) Determine mechanistically how Snrk-1/Dusp-5 participates with specific signaling pathway in vivo and in vitro. In each of these aims, we will employ a variety of cell biology, molecular and developmental biology approaches to unravel the mechanistic underpinnings of Snrk-1/Dusp-5 to TGF- signaling pathway including the role of Rock-1 in this process in vivo and in vitro. The approach is innovative because it provides us an unprecedented opportunity to understand the molecular pathway that these genes participate in vivo thereby contributing to our understanding of the mechanistic steps involved in VAs pathogenesis. The proposed research is significant because studying novel intracellular signaling molecules that participate in the mechanistic underpinnings of the TGF- signaling pathway in vasculogenesis, removes this critical barrier to progress thus moving the field of vascular biology forward. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because vascular anomalies (VAs) represent an important clinical problem that has few therapeutic options. The successful mechanistic understanding of VAs pathogenesis is likely to provide candidate targets for drug development against VAs. Thus, the proposed research is directly relevant to NIH's mission of reducing the burden of debilitating health conditions from diseases affected by deregulated vasculature.

描述（由申请人提供）：血管异常（VAS），胚胎血管发育中的先天错误分为两个不同的组：血管瘤和血管畸形（VMS）。当前对VA的疗法在功效上受到限制，并且具有重大并发症。因此，为了改善患有这些疾病的患者的治疗，确定导致VM和血管瘤发病机理的潜在机制至关重要。我们的长期目标是了解导致VA发病机理的潜在机制，以便可以产生更好的靶向这种情况的治疗剂。为了实现这一目标，这里的目的是研究我们组的两个最近鉴定的基因，即非发酵受体激酶-1（SNRK-1），一种丝氨酸 - 苏氨酸激酶和双特异性磷酸酶-5（DUSP-5）（DUSP-5）（DUSP-5）（DUSP-5），一种米特激活蛋白激酶（MAP）患者（MAP）和VMS患者，以及与Hemange and vers ins vers ins vers and vers。我们的核心假设是，“转化生长因子-beta（TGF-）配体在内皮细胞上通过SNRK-1和DUSP-5传输信号的特定受体（ALK-1/ALK-5）相互作用，以将含有蛋白质激酶-1（岩石酶-1）的共同固定的蛋白质蛋白（岩石酶-1（Rock-1）诱导细胞和周围的细胞和周围的细胞构造和周围的细胞。该假设是基于我们组的初步数据提出的，该数据在SNRK-1的基板的屏幕上确定了TGF-Signaling家族和Rock-1的几个成员（ALK-1，ALK-2，SMAD-3，BMPR-2）。拟议的研究的理由是，一旦确定了SNRK-1和DUSP-5如何调节胚胎开发过程中ECS和EC前体（血管生成）中的TGF信号传导，我们就可以针对TGF-SNRK-1/DUSP-5信号传导途径，并以重复的FDA批准药物为基于基础的患者提供了更高的选择。该假设将通过追求三个具体目的来检验：1）确定细胞自主与非自主SNRK-1/DUSP-5功能的贡献，以及DUSP-5突变在VA疾病发病机理中的作用。 2）确定岩石1在体内和体外信号传导中的机械作用。 3）从体内和体外进行特定的信号通路，从机理上确定SNRK-1/DUSP-5的参与方式。在这些目标中的每一个中，我们将采用各种细胞生物学，分子和发育生物学方法来揭示SNRK-1/DUSP-5的机械基础，从而揭示TGF信号传导途径，包括Rock-1在体内和体外的作用。该方法具有创新性，因为它为我们提供了一个前所未有的机会，可以理解这些基因参与体内的分子途径，从而有助于我们理解VAS发病机理所涉及的机械步骤。拟议的研究之所以重要，是因为研究了参与血管生成中TGF信号通路的机械基础的新型细胞内信号分子，从而消除了进展的关键障碍，从而移动了血管生物学的领域。公共卫生相关性：拟议的研究与公共卫生有关，因为血管异常（VAS）代表了一个重要的临床问题，几乎没有治疗选择。对VAS发病机理的成功机械理解很可能为针对VA的药物开发提供了候选靶标。因此，拟议的研究与NIH的使命直接相关，该使命是减轻受管制脉管系统影响的疾病的健康状况的负担。