Vascular Progenitor Cells in Neovascular AMD

描述（由申请人提供）：老年性黄斑变性（AMD）是老年人视力受损的最重要原因。黄斑变性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。新血管性AMD的发病机制是多因素的，但通常被认为是由血管生成驱动的，在这个过程中，新血管复合体的细胞成分来源于邻近的原有毛细血管细胞。然而，另一种被称为“出生后血管生成”的机制已被证明有助于某些形式的新生血管形成。在血管发生中，新血管复合体的细胞成分部分来源于骨髓来源的循环细胞。我们的团队之前已经证明，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，我们将证实并扩展这些发现，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。初步工作将在两种啮齿动物CNV模型中进行，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。分离和消耗实验将试图确定在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AMD患者的外周血中发现。在随后的实验中，我们将确认和扩展我们的初步人体发现，并且，类似于在动物身上进行的临床前工作，试图确定与疾病状态相关的循环细胞的特定亚群。这些结果将扩展到包括对接受CNV手术切除的患者的验证性实验以及随后对病变的组织学分析。此外，将进行一项病例对照的人体临床试验，以进一步将某些外周细胞的存在、缺失或相对比例与预测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。黄斑变性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。在这项提议中，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。

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.