Racial Variations in Optic Nerve Head Structure and Biomechanics

描述（由申请人提供）：眼压升高（IOP）一直被认为是造成视神经头（ONH）青光眼损害的原因。有令人信服的证据表明，在IOP水平升高时，非洲裔患者发生青光眼损害的风险要大得多。在这项提议中，我们检验了视神经头（ONH）生物力学的种族差异对这种风险差异有重要影响的假设。然而，目前尚不清楚IOP是如何引发导致视网膜神经节细胞死亡的一系列事件的。我们利用ONH的三维重建和生物力学工程原理，研究了青光眼IOP升高的力学效应。然而，非洲血统与IOP升高的机械效应之间的关系尚不清楚。ONH结构和生物力学的种族差异如何增加其对IOP的易感性？ONH结缔组织的健壮性是了解个体对青光眼易感性的关键吗？在非洲人后裔青光眼进展的风险增加中，筛板和乳头周围巩膜的结构刚度起什么作用？为了回答这些问题，我们将使用新的方法来阐明祖先与io诱导的ONH结缔组织变形之间的关系。通过“ONH生物力学”，我们指的是IOP与ONH和乳头周围巩膜中结缔组织结构刚度（组织结构和材料特性的结合）之间的相互作用。该项目的直接目标是表征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。为了实现我们的直接目标，我们将建立来自非洲和欧洲血统捐献者的ONH组织的数字三维重建，量化每次重建中的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IOP水平的生物力学反应。长期以来，人们一直认为眼压升高（IOP）在青光眼视神经头损伤（ONH）中起着致病作用，非洲人后裔的患者有更高的发病和进展风险。我们建议测量ONH结构和io诱导的生物力学反应的种族差异。然后，利用生物力学工程原理，我们将利用这些数据创建与年龄相关的IOP升高对ONH的力学影响的计算模型，以阐明非洲血统与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.