形觉剥夺性近视中巩膜重塑机制的研究

近视是全球发病率最高的屈光不正,发病机制至今不明。形觉剥夺性近视（FDM）动物模型的建立为近视的病因学研究开辟了新局面。形觉剥夺主要通过“局部视网膜机制”来调控邻近巩膜的生长。外界刺激作用于视网膜,启动视网膜一视网膜色素上皮层一脉络膜信号转导系统,把局部视网膜信号转化为调控巩膜重塑的信号,诱导细胞外基质异常表达,巩膜胶原纤维改变等,引起巩膜重塑。就FDM中不同种属动物间巩膜重塑发生的形态学变化及相关因素等做一综述。     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

视黄酸在形觉剥夺性近视眼巩膜中作用的研究

剥夺新生动物视网膜正常成像可导致轴性近视的发生,这种近视称为形觉剥夺性近视(FDM).高度近视形成过程中的眼轴过度延长及巩膜变薄,可能是受局部视网膜信息调控的巩膜细胞外基质(ECM)主动重塑的结果.巩膜主动重塑在眼球生长发育及正视化形成中起重要作用.视黄酸(RA)及其受体在FDM形成中对巩膜基质、软骨层和成纤维细胞层及基质降解相关蛋白酶的改变具有重要调节作用.它可能是调节FDM眼球伸长的信号分子,在巩膜重塑中扮演重要角色.     

Decreased proteoglycan synthesis associated with form deprivation myopia in mature primate eyes

PURPOSE: The rate of proteoglycan synthesis was measured in the scleras of adolescent marmosets that had undergone monocular form deprivation to characterize the scleral extracellular matrix changes associated with the development of myopia in a mature primate. METHODS: Form deprivation myopia was induced in adolescent marmosets by unilateral lid suture for an average of 108 days. After the lids were reopened, the axial lengths and refractions were measured at intervals for up to 39 weeks. At the end of the study period, sclera were isolated and immediately radiolabeled with 35SO4 in organ culture. Proteoglycan synthesis rates were determined by measurement of 35SO4 incorporation into cetylpyridinium chloride-precipitable glycosaminoglycans after digestion of the scleral samples with proteinase K. Collagen content was determined by measurement of total hydroxyproline in scleral digests. Newly synthesized proteoglycans were separated on a Sepharose CL-4B molecular sieve column and identified by their core proteins by Western blot analyses. RESULTS: Lid suture resulted in myopia due to a significant increase in vitreous chamber depth. After Sepharose CL-4B chromatography, newly synthesized scleral proteoglycans isolated from normal, form-deprived, and contralateral control eyes, resolved into one major peak that eluted in the position of decorin, a small chondroitin-dermatan sulfate proteoglycan. After digestion of the major peak with chondroitinase ABC, an approximately 45-kDa core protein was detected by Western blot analyses, confirming the presence of decorin. Form deprivation resulted in a significant reduction in the rate of proteoglycan synthesis in the posterior sclera (-43.55%, P < or = 0.001). Proteoglycan synthesis was also significantly reduced in the posterior sclera of form-deprived eyes relative to total collagen content (-36.19%, P < or = 0.01) and was negatively correlated with the rate of vitreous chamber elongation in the deprived eye (r2 = 0.779, P < or = 0.05). CONCLUSIONS: Significant extracellular matrix remodeling occurs in the posterior sclera of the adolescent primate eye during vitreous chamber elongation and myopia development. The negative correlation between vitreous chamber elongation rates and the synthesis rates of decorin in form-deprived eyes suggests that proteoglycan synthesis within the posterior sclera plays a role in the regulation of ocular size and refraction in the adolescent marmoset.     

Evidence that increased scleral growth underlies visual deprivation myopia in chicks

The authors evaluated three measures of scleral growth in chicks that were visually deprived with the use of translucent occluders. The authors sought to determine whether the ocular elongation and myopia that results from this deprivation is associated with increased growth of the sclera. The authors found that the dry weight of the sclera of deprived eyes increased 65% faster than that of nondeprived eyes. Furthermore, the uptake of labeled methionine and thymidine was significantly increased by visual deprivation, whether expressed as incorporation per sclera, per milligram of sclera, per milligram of protein, or per milligram of DNA. In addition, the amount of DNA and soluble protein was significantly greater in the scleras of deprived eyes than in those of nondeprived eyes. Finally, the degree of hydration of the scleras from deprived eyes was greater relative to their weight than that of the scleras from nondeprived eyes. These results suggest that visual deprivation causes increased cellular proliferation and increased protein synthesis in the sclera of chicks.     

豚鼠形觉剥夺早期后极部巩膜基质金属蛋白酶2及其抑制剂动态表达

目的探讨豚鼠形觉剥夺性近视（form-deprivation myopia, FDM ）早期后极部巩膜基质金属蛋白酶2（matrix metalloproteinase-2, MMP-2）及基质金属蛋白酶抑制剂2（tissue inhibitor of matrix metalloproteinase-2,TIMP-2）mRNA的表达。方法4周龄三色豚鼠50只,随机分成实验组和正常对照组各25只,实验组又随机分为5组,单眼形觉剥夺（monocular deprivation, MD）右眼1、4、7、14、21d制备FDM动物模型,未遮盖眼为自身对照组。各组豚鼠进行检影验光和A超测量眼轴长度。提取后极部巩膜总RNA,二步法逆转录聚合酶链反应检测各组后极部巩膜MMP-2及TIMP-2mRNA的表达水平。结果除1d外,各组MD后极部巩膜MMP-2mRNA的表达与正常对照组、自身对照组差异均有统计学意义（P〈0,05）,MD组间差异也有统计学意义（P〈0．01）;而TIMP-2mRNA的表达则逐渐下降。各自身对照组MMP-2、TIMP-2mRNA的表达与MD组变化趋势大致相同。结论MMP-2／TIMP-2之间动态平衡失调可能是启动豚鼠FDM巩膜细胞外基质早期主动重塑的重要因素。（中国跟耳鼻喉科杂志,2010,10：75—78）     

Scleral changes in chicks with form-deprivation myopia

The sclera in myopic regions of chick eyes was studied histologically and compared to the sclera in corresponding regions of normal fellow eyes. Chicks had been monocularly deprived of form vision in the nasal half of the retina from hatching. The fellow control eye and the temporal retina of the deprived eye had normal vision. With this treatment, the resulting form-deprivation myopia and eye enlargement are restricted to the retinal region that had been form deprived. We found that the cartilaginous sclera in the myopic nasal region exhibited several differences from that in the corresponding non-myopic region: it was thicker, its cell density was lower, and the number of chondrocytes and binucleate cells was higher. In contrast, the fibrous sclera was thinner. These changes suggest that form-deprivation myopia causes an increased production of extracellular matrix and an increased level of mitotic activity in the cartilaginous sclera. As expected, the non-myopic temporal regions of experimental and control eyes did not differ in any of these parameters. The findings of the present study suggest that the eye enlargement accompanying form-deprivation myopia is not the consequence of scleral stretching but of abnormal growth.     

小鸡形觉剥夺性近视眼巩膜TIMP-2 mRNA表达的时间动态变化

目的 探讨小鸡形觉剥夺性近视眼(FDM)后极部巩膜基质金属蛋白酶2组织抑制剂(TIMP-2)mRNA表达水平的动态变化。方法 取1d龄来亨雏鸡以半透明眼罩分别遮盖右眼4、7、14、21、30d制备FDM动物模型,未遮盖眼为自身对照眼,并随机选取同数目同龄小鸡作为正常对照眼。实验前及预定实验时间进行视网膜检影验光和眼轴长度测量,摘除眼球,提取后极部巩膜总RNA,采用一步法逆转录-多聚酶链反应检测每组小鸡后极部巩膜TIMP-2 mRNA表达水平。结果 与正常组、自身对照组相比,FDM后极部巩膜TIMP-2 mRNA表达明显降低,组间差异非常显著(P<0.01)。随遮盖时间延长其表达降低,7～21d降低最明显,FDM组间差异显著(P<0.01)。自身对照组TIMP-2 mRNA表达水平较同龄正常对照组存在下调趋势,但组间无统计学差异(P>0.05)。结论 后极部巩膜TIMP-2表达抑制极可能作为导致巩膜ECM主动重塑的始发因素之一而参与FDM形成。     

豚鼠实验怀近视眼巩膜的羟脯氨酸含量改变

目的：探讨胶原水平的变化在哺乳类动物近视眼发生机制中的作用。方法：出生3周的乳花色雄性豚鼠24只,单眼眼睑缝合75天后,检测影响眼轴。后极和前部巩膜分别称重后,以蛋白酶K消化和盐酸水解,用氯胺T氧化比色法测定每毫克巩膜中的羟脯酸含量。结果：豚鼠75天的形觉剥夺诱导了约－9D的相对近视和0．39mm的眼轴延长。剥夺眼部巩膜和后极巩膜的羟脯氨酸含量差异有显著性意义（P＜0．001）;对照前后巩膜的羟脯氨酸含量差异无统计学意义（P＞0．05）。双眼前部巩膜的羟脯氨酸含量差异无统计学意义（P＞0．05）;双眼后部巩膜的羟脯氨酸含量差异有显著性意义（P＜0．001）。结论：豚鼠眼形觉剥夺性近视时,主要是后极部羟脯胺酸含量减少,即后极部的巩膜胶原优先影响。由于后极部巩膜胶原减少,减弱了巩膜的抵抗力,使眼轴易于延展而发生近视。     

小鸡形觉剥夺性近视眼后极部巩膜MMP-2与TIMP-2 mRNA表达的动态变化

目的　探讨小鸡形觉剥夺性近视眼 (form deprivationmyopia,FDM )后极部巩膜基质金属蛋白酶 2 (matrixmetalloproteinase 2 ,MMP 2 )及其特异性组织抑制剂 (tissuein hibitorofmatrixmetalloproteinase 2 ,TIMP 2 )mRNA表达的时间动态性变化。方法　 5 0只 1d龄来亨雏鸡以半透明眼罩分别遮盖右眼 4、7、14、2 1、30d制备FDM动物模型 ,每组10只 ,未遮盖眼为自身对照眼 ,并随机选取同数目同龄小鸡作为正常对照眼。实验前及预定实验时间进行视网膜检影验光和眼轴长度测量。摘除眼球 ,提取后极部巩膜总RNA ,采用一步法逆转录 聚合酶链反应检测每组小鸡后极部巩膜MMP 2、TIMP 2mRNA表达水平。结果　与正常组、自身对照组相比 ,FDM后极部巩膜MMP 2mRNA显著增高 ,TIMP 2mRNA表达明显降低 ,组间差异非常显著 (P <0 .0 1)。随遮盖时间延长 ,MMP 2mRNA表达逐渐上调 ,7～ 2 1d达最高峰 ,以后轻度下降 ,但仍维持于一较高水平 ,不同遮盖时间组间差异显著 (P <0 .0 1) ,而TIMP 2mRNA表达与之相反。自身对照组MMP 2mRNA表达较同龄正常对照组有轻度上调趋势 ,TIMP 2有下调趋势 ,但组间均无统计学差异 (P >0 0 5 )。结论　MMP 2 /TIMP 2之间动态平衡失调极可能是启动小鸡FDM巩膜细胞外基质早期主动重塑的关键     

针刺对形觉剥夺性近视豚鼠巩膜形态及组织中HIF-1α、SOD、MDA水平的影响

目的 探究针刺对形觉剥夺性近视(FDM)豚鼠巩膜组织形态特点及巩膜组织中缺氧诱导因子1α(HIF-1α)、超氧化物歧化酶(SOD)、丙二醛(MDA)水平的影响。方法 选取普通级3周龄健康三色豚鼠72只,随机分为空白组、模型组和针刺组(各24只)。用半透明气球作为眼罩分别固定于模型组和针刺组豚鼠右眼及头面部建立FDM模型,左眼充分暴露作自身对照;针刺组在豚鼠模型建立当天起,于每日相同时间对豚鼠进行针刺和电针干预治疗,空白组豚鼠不做任何干预。记录每组豚鼠造模前、造模后2周及4周的眼轴长度和屈光度。造模后4周处死豚鼠,光学显微镜下观察巩膜形态变化,Western blot检测各组豚鼠巩膜中HIF-1α蛋白表达,比色法测定各组豚鼠巩膜中SOD活力和MDA含量。结果 造模后2周和4周,与空白组比较,模型组及针刺组豚鼠遮盖眼近视屈光度及眼轴长度均明显增加(均为P<0.05);与模型组比较,针刺组豚鼠遮盖眼近视屈光度减小,眼轴增长明显减缓(均为P<0.05)。造模后4周,与空白组比较,模型组豚鼠巩膜厚度明显变薄,胶原纤维分布稀疏,有明显纤维空隙且排列不规则;与模型组相比,针刺组豚鼠巩膜层...     

Structural and ultrastructural changes to the sclera in a mammalian model of high myopia

PURPOSE: The development of high myopia is associated with scleral thinning and changes in the diameter of scleral collagen fibrils in humans. In the present study, the association between these scleral changes and the losses in scleral tissue that have previously been reported in animal models were investigated to determine the relationship between changes in collagen fibril architecture and thinning of the sclera in high myopia. METHODS: Myopia was induced in young tree shrews by monocular deprivation of pattern vision for short-term (12 days) or long-term (3-20 months) periods. Scleral tissue from normal animals over a wide age range (birth to 21 months) was also collected to provide data on the normal development of the sclera. Light and electron microscopy were used to measure scleral thickness and to determine the frequency distribution of collagen fibril diameters in the sclera. Tissue loss was monitored through measures of scleral dry weight. RESULTS: Significant scleral thinning and tissue loss, particularly at the posterior pole of the eye, were associated with ocular enlargement and myopia development after both short- and long-term treatments. However, collagen fibril diameter distribution was not significantly altered after short-term myopia treatment, whereas, from 3 months of monocular deprivation onward, significant reductions in the median collagen fibril diameter were noted, particularly at the posterior pole. CONCLUSIONS: The results of this study demonstrated that loss of scleral tissue and subsequent scleral thinning occurred rapidly during development of axial myopia. However, this initial tissue loss progressed in a way that did not result in significant alterations to the collagen fibril diameter distribution. In the longer term, there was an increased number of small diameter collagen fibrils in the sclera of highly myopic eyes, which is consistent with findings in humans and is likely to contribute to the weakened biomechanical properties of the sclera that have previously been reported.     

The time course of changes in mRNA levels in tree shrew sclera during induced myopia and recovery

PURPOSE: In tree shrews, visual form deprivation produces increased axial elongation of the deprived eye and a myopic shift in refractive state. A change in scleral extensibility (creep rate) is closely associated with the change in axial elongation rate. These effects may be due to scleral tissue remodeling produced by a change in scleral gene expression. In this study, the authors investigated the time course of changes in scleral mRNA levels for selected proteins during the development of form deprivation myopia and during recovery, to determine which, if any, are temporally associated with changes in scleral extensibility and axial elongation rate. METHODS: Competitive RT-PCR was used to measure the levels of mRNA for structural proteins (collagen [alpha1(I) chain], decorin core protein), degradative enzymes (MMP-2 [gelatinase-A], MMP-3 [stromelysin-1]), and a tissue inhibitor of metalloproteinase (TIMP-1) in the scleras of tree shrews that had been subjected to 1, 2, 4, or 11 days of monocular form deprivation (MD) or 11 days of MD followed by 2 or 4 days of recovery produced by removal of the MD. Four groups of normal animals provided age-matched normal data. RESULTS: Compared with the control eyes, deprived-eye MMP-2 mRNA levels were higher and MMP-3 levels were lower after 4 days of MD. Deprived-eye collagen mRNA levels were lower than control eye levels after 11 days of MD. The differential effects produced by MD were absent after 2 days of recovery and generally were reversed after 4 days. Decorin mRNA levels in the deprived and control eyes were not significantly different during either MD or recovery. During MD, mRNA levels for collagen, MMP-3, and TIMP-1 decreased in both the deprived and control eyes, compared with age-matched normal eyes. The binocular changes in collagen and TIMP-1 mRNA levels and the differential changes in MMP-2 and MMP-3 levels were detected at least as early as axial, refractive, and creep rate changes. CONCLUSIONS: The up- and downregulation of the specific mRNAs studied, on a time course similar to that for physical changes in the sclera, suggests that modulation of gene expression by the visual environment may produce scleral remodeling and changes in scleral creep rate during the development of form deprivation myopia and recovery.