Vascular Progenitor Cells in Neovascular AMD

新生血管性 AMD 中的血管祖细胞

• 批准号: 7440769
• 负责人: SCOTT W COUSINS
• 金额: $ 39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440769
• 关键词: Actins; Adenovirus Vector; Affect; Age; Age related macular degeneration; Aging; Animal Model; Animals; Biological Assay; Blindness; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Bone Marrow Transplantation; Caliber; Case-Control Studies; Cells; Choroidal Neovascularization; Clinical Trials; Collagen; Complex; Data; Detection; Development; Disease; Donor person; Elderly; Endothelial Cells; Excision; Experimental Models; Exudative age-related macular degeneration; Fibrosis; Frequencies; Growth; Histologic; Human; Implant; In Situ; In Vitro; Label; Lasers; Lesion; Macular degeneration; Marrow; Mediating; Mesenchymal; Mus; Myofibroblast; Operative Surgical Procedures; Pathogenesis; Pathologic; Patients; Pericytes; Peripheral; Phenotype; Process; Public Health; Rattus; Relative (related person); Retina; Retinal; Rodent; Rodent Model; Severities; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Stem cells; Transplantation; Tube; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vision; Work; age related; aged; angiogenesis; base; capillary; case control; cell type; human subject; intravenous injection; matrigel; neovascularization; new growth; normal aging; peripheral blood; postnatal; pre-clinical; precursor cell; progenitor; research study; size; subretinal injection; vasculogenesis; von Willebrand Factor

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most important cause of impaired vision in the elderly. The major cause of severe vision loss in AMD is choroidal neovascularization (CNV) or the growth of new vessels under the retina. The pathogenesis of neovascular AMD is multifactorial, but in general, is considered to be driven by angiogenesis, a process in which the cellular components of the new vessel complex are derived from cells from the adjacent pre-existing capillary. However, an alternative mechanism termed "postnatal vasculogenesis", has been shown to contribute to some forms of neovascularization. In vasculogenesis, the cellular components of the new vessel complex are derived, in part, from bone-marrow derived circulating cells. Our group has previously demonstrated that CNV, in animal models, is formed in part from these bone-marrow derived cells. In this proposal, we will confirm and extend these findings to understand the contribution of the various cellular subsets within the circulation which may affect pathogenesis, progression and severity of CNV. Initial work will be done in two rodent models of CNV, the laser-induced and subretinal injection of an adenoviral vector expressing vascular endothelial growth factor. Isolation and depletion experiments will attempt to identify the specific cell types found within the rodent bone marrow which contribute to the CNV. Our group has also demonstrated that these bone-marrow vasculogenic cells can also be identified in the peripheral blood of patients with various degrees of AMD. In subsequent experiments, we will confirm and extend our preliminary human findings and, similar to the preclinical work performed in animals, attempt to identify specific subsets of circulating cells which correlate with disease status. These results will be extended to include confirmatory experiments on patients undergoing surgical excision of CNV and the subsequent histologic analysis of the lesions. In addition, a case-controlled human clinical trial will be performed to further correlate the presence, absence or relative ratios of certain peripheral cells and the ability to predict development, progression or severity of CNV in patients with AMD. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the most important cause of impaired vision in the elderly. The major cause of severe vision loss in AMD is choroidal neovascularization (CNV) or the growth of new vessels under the retina. In this proposal, we seek to understand the contribution of the various cellular subsets within the circulation which may affect pathogenesis, progression and severity of CNV.

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是老年人视力受损的最重要原因。 AMD 严重视力丧失的主要原因是脉络膜新生血管 (CNV) 或视网膜下新血管的生长。新生血管性 AMD 的发病机制是多因素的，但一般来说，被认为是由血管生成驱动的，在该过程中，新血管复合体的细胞成分源自邻近预先存在的毛细血管的细胞。然而，另一种称为“产后血管生成”的机制已被证明有助于某些形式的新血管形成。在血管生成中，新血管复合体的细胞成分部分源自骨髓来源的循环细胞。我们的小组之前已经证明，在动物模型中，CNV 部分是由这些骨髓来源的细胞形成的。在本提案中，我们将确认并扩展这些发现，以了解循环中各种细胞亚群的贡献，这些亚群可能影响 CNV 的发病机制、进展和严重程度。初步工作将在两种 CNV 啮齿动物模型中进行，即激光诱导和视网膜下注射表达血管内皮生长因子的腺病毒载体。分离和消除实验将尝试鉴定啮齿动物骨髓中发现的有助于 CNV 的特定细胞类型。我们的研究小组还证明，这些骨髓血管生成细胞也可以在不同程度的AMD患者的外周血中被识别出来。在随后的实验中，我们将确认并扩展我们的初步人类发现，并与在动物身上进行的临床前工作类似，尝试识别与疾病状态相关的特定循环细胞子集。这些结果将扩展到包括对接受 CNV 手术切除的患者进行的验证性实验以及随后对病变进行的组织学分析。此外，还将进行病例对照人体临床试验，以进一步将某些外周细胞的存在、不存在或相对比例与预测 AMD 患者 CNV 的发生、进展或严重程度的能力联系起来。公共卫生相关性：年龄相关性黄斑变性 (AMD) 是老年人视力受损的最重要原因。 AMD 严重视力丧失的主要原因是脉络膜新生血管 (CNV) 或视网膜下新血管的生长。在本提案中，我们试图了解循环中各种细胞亚群的贡献，这些亚群可能影响 CNV 的发病机制、进展和严重程度。