MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE

描述（由申请人提供）： 神经退行性疾病的特征在于有丝分裂后神经元的不可阻挡的变性，并且在很大程度上难以治疗。 这些疾病的一个重要子集，视网膜色素变性（RP），影响终末分化的神经元群体，视杆细胞，并导致失明。 与大多数其他神经退行性疾病相比，RP是由充分表征的单基因缺陷引起的，并且影响神经系统的解剖学可及部分。 该建议的中心假设是，尽管遗传病因不同，但神经元变性的机制集中在共同的关键途径上。 这些途径的鉴定将促进对神经元稳态的理解，并且是开发有效疗法的先决条件。 拟议的研究将联合收割机两种策略，以确定基因促进感光细胞死亡的多个遗传不同的小鼠模型的视网膜变性。 主要研究者（PI）在rd-1小鼠中进行了初步的cDNA阵列实验，并产生了早期感光细胞死亡期间分子事件的工作模型。 使用rd-1作为基准模型，PI将：1）评估在另外三种遗传上不同的RP模型（rds小鼠、tulpl小鼠和视紫红质突变小鼠）中是否出现相似的表达模式，2）在rd-1小鼠中消除rd-1中过表达的选定基因，并将对rd-1视网膜表型和基因表达模式的影响关联起来。 PI已经确定了三个基因[caspase-3，肿瘤坏死因子受体1（TNFR 1）和早期生长反应-1（EGR-1）]作为这种方法的候选基因，并对caspase-3进行了初步实验。 通过整合两种策略的数据，PI将能够在一种或多种RP模型中建立促进感光细胞凋亡的单个基因之间的因果关系。 进行的培训和研究将扩展和拓宽候选人以前在兽医学，解剖病理学方面的培训，以及感光障碍分子遗传学方面的研究生培训，从而实现真正的科学独立。 培训将在耶鲁大学医学院进行，由神经生物学和眼科学教授Colin Barnstable博士指导，他是国际公认的分子生物学家，使用视网膜发育和退化的小鼠模型。

DESCRIPTION (provided by applicant): Neurodegenerative diseases are characterized by inexorable degeneration of post-mitotic neurons and are largely refractory to therapy. One important subset of these diseases, retinitis pigmentosa (RP), affects a terminally differentiated neuronal population, the rod photoreceptor, and leads to blindness. In contrast to the majority of other neurodegenerative diseases, RP is caused by well-characterized single gene defects, and affects an anatomically accessible portion of the nervous system. The central hypothesis in this proposal is that despite differing genetic etiologies, mechanisms of neuronal degeneration converge upon common critical pathways. Identification of such pathways would advance understanding of neuronal homeostasis and is a prerequisite for developing effective therapies. The proposed research will combine two strategies to identify genes promoting photoreceptor death in multiple genetically distinct mouse models of retinal degeneration. The Principal Investigator (PI) has performed preliminary cDNA array experiments in the rd-1 mouse and has generated a working model of molecular events during early photoreceptor death. Using rd-1 as a benchmark model, the PI will: 1) assess whether similar expression patterns occur in three additional, genetically distinct models of RP (the rds mouse, the tulpl mouse and the rhodopsin mutant mouse) and, 2) eliminate, in the rd-1 mouse, selected genes which are overexpressed in rd-1, and correlate the effects upon the rd-1 retinal phenotype and gene expression pattern. The PI has identified three genes [caspase-3, tumor necrosis factor receptor 1 (TNFR1), and early growth response-1 (EGR-1)], as candidates for this approach, and has performed preliminary experiments with caspase-3. By integrating data from both strategies, the PI will be able to establish cause and effect relationships between individual genes that promote photoreceptor apoptosis in one or more models of RP. The training and research undertaken will extend and broaden the candidate's previous training in veterinary medicine, anatomic pathology, and graduate training in molecular genetics of photoreceptor disorders, leading to true scientific independence. Training will be undertaken at the Yale University School of Medicine under the mentorship of Dr. Colin Barnstable, Professor of Neurobiology and Ophthalmology, who is an internationally recognized molecular biologist using mouse models of retinal development and degeneration.