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The Dichotomy of Alk1 and Alk5 Signaling Pathways in Vascular Response to Injury

Alk1 和 Alk5 信号通路在血管损伤反应中的二分法

基本信息

批准号：
8847768
负责人：
Zhihua Jiang
金额：
$ 31.36万
依托单位：
UNIVERSITY OF FLORIDA
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：
2011-07-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847768
关键词：
Adult Anti-Inflammatory Agents Anti-inflammatory Attenuated Autologous Automobile Driving Behavior Biological Models Biology Blood Vessels Bypass CCL2 gene Cell Culture Techniques Cells Cellular biology Cessation of life Clinical Clinical Trials Complex Cre-LoxP Data Development Endothelial Cells Endothelium Equilibrium Evaluation Failure Fibrosis Genes Genetic Genetic Recombination Healed Human Hyperplasia Implant In Vitro Inflammatory Interleukin-6 Knowledge Laboratories Limb structure Medial Mediating Mediator of activation protein Modeling Morphology Mus Myosin Heavy Chains NF-kappa B Nature Organ Outcome Pathology Patients Performance Pharmacologic Substance Phenotype Population Process Production Property Recovery of Function Reporting Role Secondary to Signal Pathway Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Specificity Stenosis System Tamoxifen Testing Therapeutic Transforming Growth Factors Translations United States Veins Work angiogenesis cancer therapy cell type clinical application clinically relevant clinically significant cytokine genetic approach graft failure graft healing healing improved in vivo inhibitor/antagonist insight leukemic stem cell migration monolayer novel novel strategies programs promoter reagent testing receptor recombinase repaired response response to injury success therapeutic effectiveness tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Over a half million of autologous vein grafts are implanted annually in the United States. However, 30-60% of the grafts fails or develops a clinically significant stenosis within the first year, causing limb loss and death. The primary cause for early vein graft failure has been identified as neointimal hyperplasia (NIH) and compelling evidence has demonstrated that TGF-ß is a driving factor for this early failure. Unfortunately, non-selective blockade of the broad TGF-ßactivities has yielded limited success in attenuating neointimal hyperplasia formation, suggesting inhibition of the specific TGF-ß activities is required. A primary mechanism that dictates TGF-ß specificity is the activation of its type I receptors Alk1 or Alk5. Although Alk1 is expressed at very low level in mature endothelium (ECs) and medial smooth muscle cells (SMCs), existing evidence suggests that Alk1 is induced in ECs and neointimal SMCs during vein graft adaptation. Recent studies for angiogenesis and other pathologies have led to an emergence of new understanding, wherein TGF-ß signals through Alk1 and Alk5 to initiate opposing effects on regulating cellular biology. We therefore hypothesize that the response of the vascular wall to TGF-ß relies on the balance between Alk1- and Alk5- signaling in both ECs and SMCs. Insult to the vein graft wall tips the balance in both cell types towards Alk5 signaling that in turn inhibits the functional recovery of ECs and upholds an inflammatory/synthetic phenotype for SMCs, driving progressive NIH. Selectively blocking Alk5 signaling to restore this balance will improve the healing response and inhibit NIH. To test this hypothesis, this project aims to: 1) Define the role of Alk1 and Alk5 signaling in SMCs in regulating the phenotype of neointimal SMCs and vein graft morphology via a validated murine vein graft model and primary neointimal SMC culture; 2) Evaluate the impact of the competing Alk1 and Alk5 signaling in ECs on functional recovery of the repopulated EC monolayer, modulation of neoSMC phenotype, and the resultant vein graft morphology; and 3) Examine the therapeutic effectiveness of siRNA and pharmaceutical inhibition of Alk1 or Alk5 signaling on the development of NIH in murine and human vein grafts. The CreloxP system will be utilized to induce selective deletion of Alk1 or Alk5 in ECs or SMCs in adult mice, so that vein grafts with and without EC or SMC specific Alk1 or Alk5 can be created for the evaluation of the vein graft morphology, the repair of the EC monolayer, and the inflammatory phenotype of neointimal SMCs. To facilitate the clinical translation of the new knowledge generated with these genetic approaches, specific siRNA and novel pharmacological inhibitors will be applied to inhibit Alk1 and Alk5 signaling pathways in both murine and ex vivo human vein grafts. The therapeutic effectiveness of these approaches will then be evaluated using both morphologic (e.g. NIH volume) and biologic (e.g. phenotypic properties of the neointimal cells) endpoints. Completion of these aims will not only provide new insights into the fundamentals of TGF-ß biology, but also generate novel strategies to manipulate complex biologic processes such as vein graft wall adaptation.

描述（由申请人提供）：在美国每年有超过50万例自体静脉移植植入术。然而，30-60%的移植物在一年内失败或出现临床上显著的狭窄，导致肢体丧失和死亡。早期静脉移植失败的主要原因已被确定为新生内膜增生（NIH），令人信服的证据表明TGF-ß是这种早期失败的驱动因素。不幸的是，非选择性封锁的范围很广