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（VA），胚胎血管发育中的先天性缺陷分为两个不同的组：血管瘤和血管畸形（VM）。目前的 VA 疗法疗效有限，并且有严重的并发症。因此，为了改善患有这些疾病的患者的治疗，确定导致 VM 和血管瘤发病机制的潜在机制至关重要。我们的长期目标是了解导致 VA 发病机制的潜在机制，以便针对这种情况产生更好的治疗方法。为了实现这一目标，这里的目标是研究我们小组最近发现的两个基因，即蔗糖非发酵受体激酶-1 (Snrk-1)（一种丝氨酸-苏氨酸激酶）和双特异性磷酸酶-5 (Dusp -5)，丝裂原激活蛋白激酶 (MAPK) 家族，在血管瘤和 VM 患者中发生突变。我们的中心假设是“转化生长因子-β (TGF-) 配体与内皮细胞上的特定受体 (ALK-1/ALK-5) 相互作用，通过 Snrk-1 和 Dusp-5 将信号传递到共同底物 Rho 相关的、卷曲的-含有蛋白激酶-1 (Rock-1) 的线圈，可诱导该细胞及其周围细胞的特异性反应。”这一假设是根据我们小组的初步数据制定的，该小组在筛选 Snrk- 底物时鉴定了 TGF-信号传导家族的几个成员（Alk-1、Alk-2、Smad-3、BMPR-2）和 Rock-1。 1.这项研究的基本原理是，一旦确定了 Snrk-1 和 Dusp-5 在胚胎发育过程中如何调节 EC 和 EC 前体（成血管细胞）中的 TGF-信号传导，我们就可以针对 TGF-Snrk-1/Dusp-5 信号传导途径与重新利用 FDA 批准的药物，从而为 VAs 患者提供更好的基于目标的治疗选择。该假设将通过追求三个具体目标进行检验：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 疾病发病机制中的作用。 2) 确定Rock-1在体内和体外Snrk-1/Dusp-5信号传导中的机制作用。 3) 从机制上确定Snrk-1/Dusp-5如何参与体内和体外的特定信号通路。在每个目标中，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 到 TGF-信号通路的机制基础，包括 Rock-1 在此过程中体内的作用和体外。该方法具有创新性，因为它为我们提供了前所未有的机会来了解这些基因在体内参与的分子途径，从而有助于我们了解 VA 发病机制中涉及的机制步骤。这项研究意义重大，因为研究参与血管生成中 TGF 信号通路机制基础的新型细胞内信号分子，消除了这一进展的关键障碍，从而推动了血管生物学领域的发展。公共健康相关性：拟议的研究与公共健康相关，因为血管异常（VA）代表了一个重要的临床问题，但治疗选择很少。对 VA 发病机制的成功理解可能为针对 VA 的药物开发提供候选靶点。因此，拟议的研究与 NIH 的使命直接相关，即减轻因脉管系统失调影响的疾病造成的健康状况恶化的负担。