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

• 批准号: 9115995
• 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
• 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/9115995
• 关键词: Address; Adult; Blood; Blood Vessels; Cell Line; Cell physiology; Cells; Cicatrix; Clinical; Cues; Education; Embryonic Development; Endothelial Cells; Engineering; Fibrosis; Generic Drugs; Genes; Genetic Transcription; Goals; Growth; Healed; Health; Heterogeneity; Home environment; Homeostasis; Human; In Vitro; Injury; Label; Lead; Liver; Lung; Mediator of activation protein; Methods; Modeling; Molecular; Mus; Natural regeneration; Nutrient; Organ; Organogenesis; Oxygen; Participant; Pathologic; Pathway interactions; Pattern; Plumbing; Pluripotent Stem Cells; Positioning Attribute; Process; Published Comment; Recovery of Function; Research; Respiratory physiology; Role; Signal Transduction; Specific qualifier value; Stem cells; Surface; Technology; Testing; Therapeutic; Therapeutic Uses; Tissues; Training; Translating; Transplantation; Vascular Endothelial Cell; Work; Xenobiotics; adult stem cell; base; chemotherapy; healing; human disease; in vivo; injured; injury and repair; innovation; knock-down; novel strategies; novel therapeutics; organ regeneration; paracrine; programs; regenerative; repaired; research study; stem; tool; transcription factor; vascular bed

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）：器官再生承诺无限访问替换组织。器官再生的当前范式取决于成年组织限制的茎和祖细胞的移植以修复受损的器官。但是，愈合受伤的器官通常会导致纤维化，功能恢复很少。该提议挑战了普遍的观点，并测试了一种替代的免费方法，即再生也可以由组织特异性血管内皮细胞（ECS）指导，该细胞（ECS）是一种有指导的利基市场，可以促进器官再生和修复而无需促进疾病促纤维化。这个概念基于我们的发现，即血管不仅是用于氧气和养分的被动管道，而且是器官功能的活跃参与者。确实，我们的小组率先提出了一个变革性的概念，即组织特异性EC产生了一组定义的非纤维化旁分泌介质，称为“血管分泌因子”，以直接诱导器官再生而无需纤维化。然而，EC详细阐述的血管分泌因子的再生功能和曲目取决于它们起源的器官。实际上，血管分泌异质性的分子决定因素是未知的。因此，我们假设该通用，未指定的EC通过“体内教育”过程获得组织特异性功能，其中血管外提示触发转录程序。指定的EC符合条件为部署组织特异性的血管分泌生长因子，这些因子驱动器官修复而无需异常的促纤维化重塑。我们的目的是确定调节EC血管分泌功能组织规范化的转录因子（TFS），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。为了检验这种变革性的假设并将这些概念转化为临床用途，我们将解决以下目标：目标1）确定血管异质性和器官再生功能的分子决定因素；目标2）确定并验证由组织特异性EC详细阐述的分子信号和血管分泌因子，这些EC可以促进器官修复而不会引起纤维化。我们已经开发了技术来传播源自小鼠和人多能干细胞以及从羊膜细胞转录重编程的ECS的通用EC。预计拟议的工作将通过揭示EC在器官修复中的动态，组织指定的作用来推翻单功能，惰性，微脉管系统的科学概念化。拟议研究的成功完成将使您能够使用“受过教育的”，组织指定的EC，这些EC归入本地受伤的器官，并提供组织特异性的血管分泌信号来调整器官再生。另外，一旦知道，血管分泌因子就可以直接传递。这种变革性的方法开辟了研究的新治疗途径，以刺激器官维修而不会疤痕。