Deciphering molecular determinants of vascular heterogeneity for organ repair

破译器官修复血管异质性的分子决定因素

基本信息

批准号：
9327054
负责人：
Shahin Rafii
金额：
$ 61.89万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9327054
关键词：
Address Adult Blood Blood Vessels Cell Line Cell physiology Cells Cicatrix Clinical Credentialing Cues Education Embryonic Development Endothelial Cells Engineering Fibrosis Generic Drugs Genes Genetic Transcription Goals Growth Factor Health Heterogeneity Home environment Homeostasis Human In Vitro Injury Instruction Intravenous Label Liver Lung Mediator of activation protein Methods Modeling Molecular Mus Natural regeneration Nutrient Organ Organogenesis Oxygen Participant Pathologic Pathway interactions Pattern Plumbing Positioning Attribute Process Published Comment Recovery of Function Research Respiratory physiology Role Signal Transduction Specific qualifier value Stem cells Supporting Cell Surface Technology Testing Therapeutic Therapeutic Uses Tissues Training Translating Transplantation Vascular Endothelial Cell Work Xenobiotics adult stem cell base chemotherapy experimental study healing human disease human pluripotent stem cell in vivo injured injury and repair innovation knock-down novel strategies novel therapeutics organ regeneration paracrine programs public health relevance regenerative repaired tool transcription factor vascular bed virtual

项目摘要

DESCRIPTION (provided by applicant): Organ regeneration promises unlimited access to replacement tissues. The current paradigm of organ regeneration is dependent on transplantation of adult tissue-restricted stem and progenitor cells to repair the damaged organ. However, healing injured organs often leads to fibrosis with little recovery of function. This proposal challenges the prevailing viewpoint and tests an alternative complimentary approach that regeneration could also be directed by tissue-specific vascular endothelial cells (ECs) functioning as an instructive niche to promote organ regeneration and repair without provoking maladaptive fibrosis. This notion is based on our finding that blood vessels are not just the passive plumbing for delivery of oxygen and nutrients, but are active participants in organ function. Indeed, our group has pioneered the transformative concept that tissue-specific ECs produce a defined set of non- fibrotic paracrine mediators, called "Angiocrine Factors" to directly induce organ regeneration without fibrosis. Yet, regenerative function and the repertoire of angiocrine factors elaborated by ECs depend upon the organ from which they originate. Indeed, the molecular determinants of angiocrine heterogeneity are unknown. Thus, we hypothesize that generic, unspecified, ECs acquire tissue specific function by a process of "in vivo education" wherein extra-vascular cues trigger transcriptional programs. Specified ECs are credentialed to deploy tissue-specific angiocrine growth factors that drive organ repair without aberrant pro-fibrotic remodeling. Our objective here is to identify transcription factors (TFs) regulating tissue-specification of EC angiocrine function so that generic ECs can be programmed to target particular vascular beds to promote regeneration. To test this transformative hypothesis and translate these concepts for clinical use we will address the following objectives: Aim 1) Identify molecular determinants of vascular heterogeneity and organotypic regenerative function; Aim 2) Determine and validate the molecular signals and angiocrine factors elaborated by tissue-specific ECs that promote organ repair without provoking fibrosis. We have developed technologies to propagate generic ECs derived from mouse and human pluripotent stem cells and those ECs transcriptionally reprogrammed from amniotic cells. The proposed work is expected to overturn the scientific conceptualization of a monofunctional, inert, microvasculature by revealing a dynamic, tissue-specified role for ECs in organ repair. Successful completion of the proposed studies will enable therapeutic use of "educated", tissue-specified ECs that home to their native injured organs and supply tissue-specific angiocrine signals to orchestrate organ regeneration. Alternatively, once known the angiocrine factors could be delivered directly. This transformative approach opens new therapeutic avenues of research to stimulate organ repair without scarring.

描述（由申请人提供）：器官再生有望无限制地获得替代组织。目前的器官再生模式依赖于移植成人组织限制性干细胞和祖细胞来修复受损器官。然而，愈合受伤的器官往往会导致纤维化，而功能几乎无法恢复。该提案挑战了主流观点，并测试了另一种补充方法，即再生也可以由组织特异性血管内皮细胞（EC）引导，作为指导性生态位，促进器官再生和修复，而不引起适应不良纤维化。这一概念基于我们的发现，即血管不仅是输送氧气和营养物质的被动管道，而且是器官功能的积极参与者。事实上，我们的团队开创了一种变革性的概念，即组织特异性内皮细胞产生一组明确的非纤维化旁分泌介质，称为“血管分泌因子”，可直接诱导器官再生而不发生纤维化。然而，内皮细胞的再生功能和血管分泌因子的全部成分取决于它们起源的器官。事实上，血管分泌异质性的分子决定因素尚不清楚。因此，我们假设通用的、未特指的内皮细胞通过“体内教育”过程获得组织特异性功能，其中血管外线索触发转录程序。特定的 EC 被证明可以部署组织特异性血管生成生长因子，从而驱动器官修复，而不会出现异常的促纤维化重塑。我们的目标是确定调节 EC 血管分泌功能的组织特异性的转录因子 (TF)，以便可以对通用 EC 进行编程以靶向特定的血管床以促进再生。为了测试这一变革性假设并将这些概念转化为临床应用，我们将实现以下目标：目标 1) 识别血管异质性和器官再生功能的分子决定因素；目标 2) 确定并验证组织特异性 EC 所产生的分子信号和血管生成因子，促进器官修复而不引发纤维化。我们开发了技术来繁殖源自小鼠和人类多能干细胞的通用 EC，以及从羊膜细胞转录重编程的 EC。这项拟议的工作有望通过揭示内皮细胞在器官修复中的动态、组织特异性作用，推翻单功能、惰性、微血管系统的科学概念。拟议研究的成功完成将使“受过教育的”组织特异性内皮细胞的治疗用途成为可能，这些内皮细胞可以归巢于其天然受损器官，并提供组织特异性血管分泌信号来协调器官再生。或者，一旦知道血管分泌因子就可以直接递送。这种变革性方法开辟了新的治疗研究途径，可刺激器官修复而不留疤痕。