Role of Egfl7 in Angiogenesis and Vascular Injury

Egfl7 在血管生成和血管损伤中的作用

• 批准号: 8297503
• 负责人: Heidi Stuhlmann
• 金额: $ 42.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297503
• 关键词: Address; Adult; Affect; Architecture; Binding; Biochemical; Biological; Blood Cells; Blood Vessels; Bone Marrow; Cardiovascular system; Cells; Chemicals; Clinic; Coculture Techniques; Development; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Epidermal Growth Factor; Extracellular Matrix; Fluorouracil; Goals; Growth; Hematopoiesis; Hematopoietic; Homeostasis; Human; Injury; Ischemia; Lead; Life; Maintenance; Modeling; Molecular; Myelosuppression; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Organism; Pathologic Neovascularization; Pathologic Processes; Physiologic Neovascularization; Play; Process; Protein Binding; Proteins; Recovery; Retina; Role; Signal Transduction; Solid Neoplasm; Stem cells; Stimulus; System; Testing; Tissues; Tumor Angiogenesis; Vascular Endothelial Growth Factors; angiogenesis; autocrine; base; chemotherapy; extracellular; in vivo; injured; injury and repair; irradiation; loss of function; mouse model; notch protein; overexpression; paracrine; progenitor; repaired; response; response to injury; tumor growth; tumor vascular supply

DESCRIPTION (provided by applicant): Angiogenesis is crucial for the development of a functional circulatory system in the vertebrate embryo. Central to these processes are the endothelial cells (EC) that form a continuous layer lining the blood vessels and constitute a dynamic system that changes in response to environmental stimuli. Epidermal growth factor-like 7 (EGFL7) is expressed by EC and is present both in soluble of ECM-bound forms and may act both in an autocrine and paracrine manner. Expression in adult endothelium is low but becomes induced during physiological and pathological angiogenesis. We have previously shown that Egfl7 is a critical, pro-angiogenic regulator of angiogenesis during embryonic development and in during post-natal angiogenesis in the retina. The mechanisms by which Egfl7 signals are transduced are not well understood. However, our studies show in vivo, that EGFL7 interacts with endothelial Notch and modulates Notch intracellular signaling. Little is known about its role in response to microvascular injury and repair. The bone marrow (BM) vasculature is an ideal model to address these questions because injury and regeneration of the sinusoidal endothelium and the HSPC residing in the vascular niche can be studied in a well-defined setting. Importantly, this model is relevant for pathological angiogenesis i.e. during tissue damage, ischemia, and tumor angiogenesis. A central hypothesis of this proposal is that EGFL7 acts in response to injury of the BM vasculature to promote endothelial and hematopoietic regeneration that restores the damaged tissue. We further propose that EGFL7 acts through an autocrine mechanism to promote neoangiogenesis in response to vascular injury via cross-talk with VEGF and Notch, and that EGFL7 acts through a paracrine mechanism as an "angiocrine factor" secreted by sinusoidal EC in the BM vascular niche to promote hematopoiesis. We will test these hypotheses in three specific aims. First, we will determine the role of Egfl7 in the BM vascular niche. Second, we will investigate the molecular and biochemical basis of Egfl7 signaling in primary human EC. Third, we will identify mechanisms of EGFL7 signaling in the BM vascular niche. Endothelial cells constitute a dynamic system that changes in response to environmental stimuli, including injury of the microvasculature. Understanding how these processes are orchestrated in a living organism may lead to treatments in which endothelial cells aid the repair of damaged vessels or restrict the blood supply of tumors. PUBLIC HEALTH RELEVANCE: The project will investigate the role of epidermal growth factor-like protein 7 (EGFL7) in angiogenesis and vascular injury. EGFL7 is a protein that is expressed by endothelial cells of blood vessels and is present both in a soluble form and bound to the extracellular matrix. This proposal will investigate how EGFL7 supports growth and maintenance of the proper architecture of specialized blood vessels and blood cells in the bone marrow. We will also determine how EGFL7 facilitates the regenerating of functional bone marrow blood vessels and blood cells after injury by myelosuppressive treatment with chemicals and irradiation. We anticipate that the protein may proof useful in the clinic to aid in recovery from chemotherapy, heart attack and ischemia and may provide a means to inhibit the growth of solid tumors.

描述（申请人提供）：血管生成对于脊椎动物胚胎中功能循环系统的发展至关重要。这些过程的核心是内皮细胞（EC），形成了血管内衬的连续层，并构成了一种动态系统，该系统会随着环境刺激的响应而变化。 表皮生长因子样7（EGFL7）由EC表达，并且以ECM结合形式的可溶性形式存在，并且可以以自分泌和旁分泌方式起作用。成年内皮中的表达较低，但在生理和病理血管生成过程中会诱导。我们先前已经表明，EGFL7是视网膜中胚胎发育和产后血管生成期间血管生成的关键，亲血管生成的调节剂。 EGFL7信号被转导的机制尚不清楚。然而，我们的研究表明，EGFL7与内皮缺口相互作用并调节凹口内信号传导。关于其对微血管损伤和修复的作用知之甚少。骨髓（BM）脉管系统是解决这些问题的理想模型，因为可以在明确定义的环境中研究正弦内皮的损伤和再生HSPC。重要的是，该模型与病理血管生成有关，即在组织损伤，缺血和肿瘤血管生成期间。该提案的一个核心假设是，EGFL7响应BM脉管系统的损伤，以促进内皮和造血再生，从而恢复受损组织。我们进一步提出，EGFL7通过一种自分泌机制起作用，以通过与VEGF和Notch的串扰对血管损伤促进新血管生成，而EGFL7通过旁乳氨酸机制作为“血管分泌因子”作为一种“血管分泌因子”，作为一种由Sinusoidal EC分泌的BM血管血管niche中的Sinusoidal EC，以促进血管促进血压。 我们将以三个特定目标来检验这些假设。首先，我们将确定EGFL7在BM血管生态位中的作用。其次，我们将研究原代人EC中EGFL7信号的分子和生化基础。第三，我们将确定BM血管生态位EGFL7信号传导的机制。 内皮细胞构成一个动态系统，该系统会随着环境刺激的响应而变化，包括微脉管系统的损伤。了解这些过程如何在活生物体中策划可能会导致治疗，其中内皮细胞有助于修复受损的血管或限制肿瘤的血液供应。 公共卫生相关性：该项目将研究表皮生长因子样蛋白7（EGFL7）在血管生成和血管损伤中的作用。 EGFL7是一种由血管内皮细胞表达的蛋白质，并以可溶性形式存在并且与细胞外基质结合。该建议将研究EGFL7如何支持骨髓中专用血管和血细胞适当结构的生长和维护。我们还将确定EGFL7如何通过通过化学物质和辐照治疗损伤后的功能性骨髓血管和血细胞再生。我们预计该蛋白质可以证明在诊所中有助于从化学疗法，心脏病发作和缺血中恢复，并可能提供抑制实体瘤生长的手段。