Interactive effects of OSA and T2DM on corneal and ocular surface disease

描述(申请人提供)：阻塞性睡眠呼吸暂停(OSA)和2型糖尿病(T2 DM)是影响全球数百万患者的流行病和共病。虽然OSA和T2 DM之间的复杂关系仍然知之甚少，但OSA和T2 DM相关并发症的病理生理变化表明重叠的、协同的机制。重要的是，这两种情况都有严重的眼部并发症报道。T2 DM已被认为是成人失明的主要原因，包括由糖尿病角膜神经病变引起的慢性、通常是疼痛的角膜并发症。研究T2 DM高血糖对角膜神经影响的研究有限，因为目前的研究未能解决OSA等共存条件的交互影响。最近，OSA、T2 DM和糖尿病周围神经病变之间的潜在联系已被发现。这个R21项目的目标是识别和描述OSA、T2 DM和病理性角膜神经变化之间的新关系，这可能有助于我们减轻OSA对角膜和眼表疾病的潜在相加影响。在这项提案中，我们将检验两个新的假设：(1)OSA患者的角膜神经形态发生改变，导致角膜和眼表的病理性变化；(2)OSA和T2 DM之间的相互作用加剧了高血糖对角膜基底下神经丛(SBNP)的有害影响，导致合并疾病的患者眼表损害增加。我们将在AIM 1中使用活体共聚焦显微镜测试这些假设，以与健康对照组相比，研究OSA、T2 DM和并存疾病患者潜在的角膜神经和上皮细胞变化。在目标2中，我们将检查与SBNP变化相关的潜在系统变量，并评估SBNP变化对眼表的后续影响。这项探索性的建议利用一个综合的多学科团队方法来研究OSA在糖尿病角膜神经病变中的新的贡献作用。与1型疾病不同，现有证据表明，仅靠血糖控制不足以阻止T2 DM的神经性并发症。这项研究将首次确定OSA是否改变了角膜神经形态，并为深入了解与OSA相关的潜在炎症和免疫学机制提供了帮助，这些机制有助于糖尿病患者角膜神经损害的病理生理学。纳入与T2 DM相关的共病疾病代表了理解糖尿病引起的神经丢失的生物学的一种创新的临床方法。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) and Type 2 diabetes mellitus (T2DM) are epidemic, comorbid conditions which affect millions of patients worldwide. While the complex relationship between OSA and T2DM is still poorly understood, the pathophysiological changes that underlie OSA and T2DM-related complications indicate overlapping, synergistic mechanisms. Importantly, severe ocular complications have been reported with both conditions. T2DM has been identified as a leading cause of adult blindness, including chronic, often painful, corneal complications resulting from diabetic corneal neuropathy. Research investigating the effects of hyperglycemia in T2DM on corneal nerves is limited, as current studies have failed to address the interactive effects of co-existent condition such as OSA. Recently, a potential link between OSA, T2DM and diabetic peripheral neuropathy has been identified. The goal of this R21 project is to identify and characterize novel relationships between OSA, T2DM and pathological corneal nerve changes that may help us to mitigate the potentially additive effects of OSA on corneal and ocular surface disease. In this proposal, we will test two novel hypotheses: (1) that corneal nerve morphology is altered in patients with OSA resulting in pathological corneal and ocular surface changes; and (2) that the interaction between OSA and T2DM exacerbates the deleterious effects of hyperglycemia on the corneal subbasal nerve plexus (SBNP), leading to increased ocular surface damage in patients with comorbid disease. We will test these hypotheses in Aim 1 using in vivo confocal microscopy to investigate potential corneal nerve and epithelial cell changes in patients with OSA, T2DM and comorbid disease compared to healthy controls. In Aim 2, we will examine potential systemic variables that are associated with alterations in the SBNP and assess the subsequent effects of changes in the SBNP on the ocular surface. This exploratory proposal utilizes a comprehensive multidisciplinary team approach to investigate a novel contributory role for OSA in diabetic corneal neuropathy. Unlike Type 1 disease, available evidence suggests that glycemic control alone is not sufficient to halt the neuropathic complications of T2DM. This study will establish, for the first time, whether corneal nerve morphology is altered in OSA and provide insight into the potential inflammatory and immunological mechanisms associated with OSA that contribute to the pathophysiology of corneal nerve damage in diabetic disease. The inclusion of co-morbid disease associated with T2DM represents an innovative clinical approach towards understanding the biology of diabetic-induced nerve loss.