Endothelial Plasticity in Human Disease

人类疾病中的内皮可塑性

• 批准号: 8648797
• 负责人: OLIN D. Liang
• 金额: $ 38.96万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648797
• 关键词: ACVR1 gene; Adipocytes; Adipose tissue; Birth; Blood Vessels; CCL2 gene; Caucasians; Caucasoid Race; Cell Differentiation process; Cells; Child; Cicatrix; Common Neoplasm; Data; Development; Disease; Doxycycline; Endothelial Cells; Fatty acid glycerol esters; Goals; Hemangioma; Implant; Infiltration; Inflammatory; Insulin-Like Growth Factor I; Invaded; Knowledge; Lead; Lesion; Life; Mediating; Mesenchymal; Mesenchymal Stem Cells; Molecular; Multipotent Stem Cells; Mus; Neoplasms in Vascular Tissue; Pathologic Processes; Patients; Phase; Phenotype; Physiological Processes; Population; Primary Cell Cultures; Process; Proliferating; Role; Stem cells; Testing; Time; Tissues; Transgenic Mice; angiogenesis; base; cadherin 5; cytokine; human disease; human tissue; in vivo; infancy; insight; lipid biosynthesis; macrophage; mouse model; mutant; neoplastic; novel; novel therapeutics; receptor; stem; tumor; tumor growth; vessel regression

Hemangiomas are vascular tumors formed by uncontrolled angiogenesis. These neoplastic lesions appear approximately 2 weeks after birth, proliferate over the following year, then subsequently undergo a slow period of involution (regression). Although some breakthroughs in understanding the molecular mechanisms that induce the proliferative phase of hemangioma progression have been made, little is known about why these tumors naturally regress. Adipogenesis is a prevalent mechanism during the involuting phase, as vascular tissue is replaced by fat tissue. However, significant insights into the molecular basis of this process do not exist. Our long-term goal is to gain an understanding of the mechanisms that cause hemangioma regression. This knowledge may lead to development of novel therapies for treatment of vascular tumors and other diseases. We hypothesize that macrophage infiltration into hemangiomas induces endothelial to mesenchymal transition (EndMT), and that these endothelial-derived mesenchymal cells take on a multipotent stem cell-like phenotype and differentiate into adipocytes to mediate hemangioma involution. The specific aims are: 1. To determine whether macrophages promote endothelial to mesenchymal transition as a mechanism of hemangioma regression. We suspect that elevated expression of MCP-1 causes recruitment of macrophages into involuting hemangiomas. We hypothesize that these macrophages secrete TGF-β2, which will induce hemangioma endothelial cells to undergo endothelial to mesenchymal transition. 2. To determine if cells formed by endothelial to mesenchymal transition acquire a stem cell phenotype and differentiate into adipocytes during hemangioma regression. We hypothesize that endothelial to mesenchymal transition forms multipotent stem-like cells in hemangiomas. We predict that cytokines such as IGF-1 are secreted from macrophages to induce differentiation of these stem-like cells into adipocytes during hemangioma involution. 3. To generate a mouse model of endothelial to mesenchymal transition. We propose to produce doxycycline inducible wild-type and mutant (constitutively active) ALK2-RFP transgenic mice that will be crossed with VE-Cadherin-Cre;Rosa26-rtTA-EGFP mice in order to selectively induce and track EndMT and subsequent cell differentiation in vivo. This will allow us to further investigate the role of EndMT in vascular regression and other physiological or pathological processes in vivo.

血管瘤是由不受控制的血管生成形成的血管瘤。这些肿瘤病变 出生后大约2周出现，第二年增殖，然后慢慢进行 涉及时期（回归）。尽管在理解分子机制方面有些突破 诱导血管瘤进展的增殖阶段已经得到了 这些肿瘤自然会退缩。掺杂阶段是一种普遍的机制，AS 血管组织被脂肪组织取代。但是，对这一过程的分子基础的重大见解 不存在。我们的长期目标是了解引起血管瘤的机制 回归。这种知识可能导致开发新的疗法，用于治疗血管肿瘤和 其他疾病。我们假设巨噬细胞浸润到血管瘤中诱导内皮 间充质转变（EndMT），并且这些内皮衍生的间充质细胞采用多能 干细胞样的表型，并分化为脂肪细胞，以介导血管瘤的不良。具体目标 是： 1。确定巨噬细胞是否将内皮促进到间充质转变为机制 血管瘤回归。我们怀疑MCP-1的表达升高会导致招募 巨噬细胞涉及血管瘤。我们假设这些巨噬细胞分泌TGF-β2， 将诱导血管瘤内皮细胞进行间充质转变的内皮。 2。确定细胞是否由内皮形成到间充质转变会获得干细胞表型 并分化为血管瘤消退期间的脂肪细胞。我们假设这种内皮 间充质转变形成血管瘤中的多能样细胞。我们预测细胞因子等 IGF-1从巨噬细胞中分泌，以诱导这些干细胞的分化为脂肪细胞。 血管瘤的反应。 3。生成内皮的小鼠模型到间充质跃迁。我们建议生产 强力霉素可诱导的野生型和突变体（组成型活性）ALK2-RFP转基因小鼠将是 与ve-cadherin-cre交叉; rosa26-rtta-egfp小鼠，以选择性地诱导和跟踪Endmt和 随后的体内细胞分化。这将使我们能够进一步研究EndMT在血管中的作用 在体内回归和其他生理或病理过程。