多巴胺转运体对近视眼形成的核素示踪受体显像研究

Dopamine transporter (DAT) were correlated with a variety of neuropsychiatric disorders such as Parkinson’s disease (PD), Alzheimer’s disease, schizophrenia, attention deficit disorder, drug abuse. At present, dopamine transporter（DAT) has seldom been reported in in-vivo studies of experimental myopia and has not been confirmed by radionuclide tracing in our knowledge. In the research of Parkinson's disease and drug addiction with PET, applicants found that 18F-FECNT had high specificity and high affinity with DAT. A preliminary researches on retinal dopamine transporter (DAT) in the experimental myopia showed that retinal DAT reduced in the development of myopia. Radionuclide tracing method will be used to detect and analyze the DAT distributions and changes in the normal and myopic eyes with specific radioactive ligand of DAT as in-vivo marker. DAT ligand β-CIT will be used to do blocking intervention by ex-vivo autoradiography and micro-PET imaging. Normal and myopic and DAT blocking intervention animal retinal DAT distribution will be obtained by analyzing the results. Micro-PET imaging, autoradiography and other techniques will be applied to study. The objective is to analyze and compare DAT changes (higher or lower?)in normal, myopic eyes and blocker intervention in order to find the relationship between DAT reduction and induced ametropia, the relationship between DAT reduction and severity of myopia and the relationship between retinal DAT reduction and DOPAC and tyrosine hydroxylase (TH) to confirm whether DAT can represent a meaningful messenger for observing eye growth and be a sensitive marker for the occurrence of myopia. This is a novel progress, which span from DA (D1, D2 receptors) and enzymes in vitro biochemical detection technology to DAT in vivo research molecular tracer study of the visual image and influence of DAT intervention to myopia.

目前多巴胺转运体DAT已成功应用于神经系统疾病等研究中，对近视眼的DAT的研究国内外尚刚刚开始。申请者对帕金森病及药物成瘾研究中发现DAT示踪剂18F-FECNT具有高特异性和高亲和力。近视眼的99mTc-TRODAT-1的micro-SPECT显像研究中发现在近视眼形成过程中视网膜DAT减少。本研究拟进一步利用18F-FECNT通过Micro-PET显像、放射自显影等对正常、不同程度近视及其DAT阻断状态下的DAT分布及变化进行定量分析研究，以此来判断DAT减少与诱导产生的屈光不正的相关性以及与近视眼严重程度增加的关系，并进一步探讨近视形成中DAT的减少与DA的分解代谢产物DOPAC及其合成限速酶酪氨酸羟化酶的关系。本课题的创新之处在于从视网膜DA及其酶的体外生化检测研究跨度到活体内分子示踪的可视图像研究，进行阻断对照试验观察阻断DAT对近视形成的影响，探讨DAT在近视形成机制中的作用。

通过对正常豚鼠进行18F-FECNT小动物PET显像及放射自显影显像，获得18F-FECNT在正常豚鼠视网膜及纹状体内的分布及动态变化特点。以此为基础，通过对豚鼠单眼佩戴眼罩的方法来建立近视眼动物模型，并采用18F-FECNT对近视眼模型组和正常对照组豚鼠进行Micro-PET分子显像，使用影像学方法证实了多巴胺转运体（dopamine transporter, DAT）在近视眼中的表达水平降低。同时，使用18F-FP-(+)-DTBZ对豚鼠视网膜上对多巴胺的贮存和释放起关键作用的囊泡单胺转运体2（vesicular monoamine transporter 2，VMAT2）进行Micro-PET显像，发现VMAT2受体在近视眼及早期糖尿病视网膜病变视网膜中表达显著降低。证实了PET/CT显像在眼科疾病中应用的可行性。.本课题相关研究成果共发表SCI论文2篇，待发表2篇。培养博士生3名。