Vascular Progenitor Cells in Neovascular AMD

新生血管性 AMD 中的血管祖细胞

• 批准号: 7586099
• 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/7586099
• 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; 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; public health relevance; research study; 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）：与年龄相关的黄斑变性（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血管形成（CNV）或视网膜下新容器的生长。新血管AMD的发病机理是多因素的，但通常被认为是由血管生成驱动的，该过程是新容器复合物的细胞成分从相邻的预先存在的毛细管中得出的。然而，一种称为“产后血管生成”的替代机制已被证明会导致某些形式的新血管形成。在血管生成中，新血管复合物的细胞成分部分是从骨髓衍生的循环细胞中得出的。我们的小组以前已经证明，在动物模型中，CNV部分由这些骨髓衍生的细胞形成。在此提案中，我们将确认并扩展这些发现，以了解循环中各种细胞子集的贡献，这可能会影响CNV的发病机理，进展和严重程度。最初的工作将在CNV的两个啮齿动物模型中进行，即激光诱导的和视网膜下注射腺病毒载体，表达血管内皮生长因子。分离和耗尽实验将尝试识别啮齿动物骨髓中发现的特定细胞类型，从而有助于CNV。我们的小组还表明，在具有不同程度的AMD的患者的外周血中也可以鉴定出这些骨髓血管生成细胞。在随后的实验中，我们将确认并扩展我们的初步人类发现，并且类似于动物在动物中进行的临床前工作，试图识别与疾病状况相关的循环细胞的特定子集。这些结果将扩展到包括对CNV手术切除的患者以及随后对病变的组织学分析的确认实验。此外，将进行一项病例对照的人类临床试验，以进一步将某些外围细胞的存在，不存在或相对比率以及预测AMD患者中CNV的发育，进展或严重程度的能力。公共卫生相关性：与年龄相关的黄斑变性（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血管形成（CNV）或视网膜下新容器的生长。在此提案中，我们试图了解循环中各种细胞子集的贡献，这可能会影响CNV的发病机理，进展和严重程度。