Racial Variations in Optic Nerve Head Structure and Biomechanics

描述（由申请人提供）：长期以来一直认为眼内压（IOP）升高是视神经乳头（ONH）昏迷性损伤的原因。有令人信服的证据表明，非洲裔患者在IOP水平升高时发生青光眼损害和进展的风险更大。在这项建议中，我们测试的假设，种族差异的视神经乳头（ONH）生物力学的重要贡献，这种差异的风险。然而，目前尚不清楚IOP如何触发导致视网膜神经节细胞死亡的级联事件。使用三维（3D）重建的ONH，和生物力学工程的原则，我们已经研究了青光眼眼压升高的机械效应。然而，非洲血统与IOP升高的机械效应之间的关系仍不清楚。ONH结构和生物力学的种族差异如何增加其对IOP的敏感性？ONH结缔组织的坚固性是了解个体青光眼易感性的关键吗？筛板和视乳头周围巩膜的结构刚度在非洲裔患者青光眼进展风险增加中起什么作用？为了回答这些问题，我们将使用新的方法来阐明祖先和IOP诱导的ONH结缔组织变形之间的关系。“ONH生物力学”是指在ONH和视乳头周围巩膜中IOP和结缔组织结构刚度（组织结构和材料性质的组合）之间的相互作用。该项目的直接目标是描述ONH生物力学的种族差异，并阐明其对ONH易感性的影响。我们的长期目标是开发临床诊断和干预措施，旨在管理青光眼发展和进展中的每个重要生物力学风险因素。为了实现我们的近期目标，我们将建立来自非洲和欧洲血统供体的人类ONH组织的数字三维重建，量化每个重建中的ONH结缔组织结构，并建立ONH结缔组织的计算有限元模型，以估计其对正常和升高的IOP水平的生物力学反应。长期以来，人们一直认为眼内压（IOP）升高是导致视神经乳头（ONH）昏迷性损伤的原因，非洲裔患者发生和进展该疾病的风险更高。我们建议测量ONH结构和IOP诱导的生物力学反应的种族差异。然后，使用生物力学工程的原则，我们将使用这些数据来创建年龄相关的机械作用的IOP升高的ONH的计算模型，以阐明非洲血统和青光眼易感性之间的联系。

DESCRIPTION (provided by applicant): Elevated intraocular pressure (IOP) has long been assumed to play a causative role in glaucomatous damage to the optic nerve head (ONH). There is compelling evidence to suggest that patients of African descent are at much greater risk for the onset and progression of glaucomatous damage at elevated levels of IOP. In this proposal, we test the hypothesis that racial differences in optic nerve head (ONH) biomechanics importantly contribute to this difference in risk. It is still unclear, however, how IOP triggers the cascade of events that lead to retinal ganglion cell death. Using three-dimensional (3D) reconstructions of the ONH, and principles of biomechanical engineering, we have studied the mechanical effects of elevated IOP in glaucoma. However, the relationship between African ancestry and the mechanical effects of elevated IOP is still unclear. How do racial variations in ONH structure and biomechanics increase its susceptibility to IOP? Is the robustness of the ONH connective tissues the key to understanding individual susceptibility to glaucoma? What role does the structural stiffness of the lamina cribrosa and peripapillary sclera play in the increased risk for glaucomatous progression in patients of African descent? To answer these questions, we will use novel methods to elucidate the relationship between ancestry and the IOP-induced deformation of ONH connective tissues. By "ONH biomechanics" we mean the interactions between IOP and connective tissue structural stiffness (the combination of tissue architecture and material properties) in the ONH and peripapillary sclera. The immediate goals of this project are to characterize racial variations in ONH biomechanics and elucidate their effects on ONH susceptibility. Our long-term goal is to develop clinical diagnostics and interventions designed to manage each important biomechanical risk factor in the development and progression of glaucoma. To accomplish our immediate goals, we will build digital three-dimensional reconstructions of human ONH tissues from donors of African and European descent, quantify the ONH connective tissue architecture within each reconstruction, and build computational finite element models of the ONH connective tissues to estimate their biomechanical response to normal and elevated levels of IOP. PUBLIC HEALTH RELEVANCE Elevated intraocular pressure (IOP) has long been assumed to play a causative role in glaucomatous damage to the optic nerve head (ONH), and patients of African descent have higher risk of development and progression of the disease. We propose to measure the racial variation in ONH structure and IOP-induced biomechanical response. Then, using the principles of biomechanical engineering, we will use these data to create computational models of the age-related mechanical effects of elevated IOP on the ONH to elucidate the link between African ancestry and glaucomatous susceptibility.