Integrating cell sorting and tissue shaping mechanisms during cornea maturation

描述(申请人提供)：角膜扩张症，一种前眼的扭曲和变薄，在2000年的总人口中有1人患有此病。其动力机制尚不清楚，部分原因是其多样性和多效性的环境和遗传原因。虽然大多数人都有治疗方案，但这种方法主要是作为短期补片，可能导致恶化的渐进性回归，通常在两年后出现。因此，一个主要的挑战是更好地了解退变条件下和治疗后的长期粘弹性反应。研究人员正在开发不同的范例，其中包括表征疾病易感性、量化诊断方法、表征伤口愈合/纤维化行为、设计人工材料和分离用于替代的干/祖细胞，以及通过对可影响角膜结构的生物力学参数进行建模来影响材料特性。我们正在利用实验、成像和计算相结合的方法开发一个同时进行的脊椎动物角膜成熟模型。我们的研究重点是了解哺乳动物角膜中一种特殊的螺旋分离行为。这种行为已经在角膜表面、上皮细胞和迁移的神经延伸中观察到。重要的是，它在圆锥角膜患者身上受到干扰，这是一种扩张性疾病。这些观察结果表明，存在一种共同的力量推动细胞分离和组织成形。我们建议使用三种不同的脊椎动物模式生物来开发一种集合度量来量化螺旋涌现的速度。发展一种特殊的分形特征作为一种分类方案，有可能补充用于诊断亚临床圆锥角膜的离散指标。为了满足询问影响角膜曲率的生物力学参数的需要，我们将利用遗传和生物医学技术的现代进步来研究微管在影响上皮细胞分离行为中的作用。我们的建议旨在开发一个平台，在该平台上整合上皮层和现有的基质模型，以更好地了解影响屈光回归和适应性反应的系统网络的整合。 公共卫生相关性：欣喜若狂的眼病是一种角膜扭曲和变薄的疾病，诊断和治疗的一个主要问题是我们缺乏对导致其长期退化的因素的了解，即形状的逐渐变化。我们正在开发一种定量的、并行的、可执行的脊椎动物角膜成熟模型，试图确定上皮细胞施加的细胞内运动是否会影响这一过程。我们希望这种将角膜上皮作为一个完整的前房网络的显性治疗将导致更好的人眼虚拟模型，从而支持新的治疗方法和亚临床诊断的发展。

DESCRIPTION (provided by applicant): Corneal ectasia, a warping and thinning of the anterior eye, afflicts 1 in 2000 of the general population. Its dynamic mechanism remains poorly understood, in part, due to its diverse and pleiotropic environmental and genetic causes. While treatment options are available to most, such methods primarily act as near-term patches that can lead to worsened progressive regression, which typically appears two years later. Therefore, a primary challenge is to better understand the long-term visco-elastic response in degenerative conditions and after treatment. Diverse paradigms are being developed in which investigators are focusing on characterizing disease susceptibility, quantifying measures for diagnoses, characterizing wound-healing/fibrotic behaviors, designing artificial materials and isolating stem/progenitor cells for replacement, and affecting material properties through modeling of biomechanical parameters that can affect corneal structure. We are developing a concurrent model of vertebrate cornea maturation using a combination of experiment, imaging and computation. Our studies focus on understanding a peculiar spiral segregation behavior that operates in mammalian corneas. The behavior has been observed across the corneal surface, in epithelial cells and migrating neural extensions. Importantly, it is disrupted in patients with keratoconus, an ectatic condition. These observations suggest the existence of a common force driving cell segregation and tissue shaping. We propose to develop an ensemble metric to quantify the rate of spiral emergence using three different vertebrate model organisms. The development of a specific fractal signature serves as a classification scheme and has the potential to complement discrete measures by which to diagnose subclinical keratoconus. To address a need to interrogate biomechanical parameters that affect corneal curvature, we will utilize modern advancements in both genetic and biomedical technologies to examine the role of microtubules in affecting epithelial cell segregation behaviors. Our proposal seeks to develop a platform upon which to integrate the epithelial layer with existing stromal models to better understand the integration of systemic networks that affect refractive regression and the adaptive response. PUBLIC HEALTH RELEVANCE: A primary problem with diagnosis and treatment of ecstatic eye disease, which is a warping and thinning of the cornea, is our lack of understanding of the factors that contribute to its long-term regression, a gradual change in shape. We are developing a quantitative, concurrent, executable model of vertebrate cornea maturation that seeks to determine whether intracellular motion exerted by epithelial cells can affect this process. We hope such explicit treatment of the corneal epithelium as an integrated network with the rest of the anterior chamber will lead to better virtual models of the human eye, which can support development of novel therapeutics and subclinical diagnoses.