Gene Expression Profiles of Retinal Degeneration

描述（由申请人提供）：许多最终导致失明的疾病是由感光细胞（PR）退化引起的。视锥细胞通常在视杆细胞之后死亡，其动力学多少取决于特定的疾病。视杆细胞丢失后视锥细胞丢失也见于遗传病因尚未确定的病例，如某些形式的黄斑变性。虽然人类在没有视杆细胞的情况下也能很好地工作，但视锥细胞介导的视觉的丧失是毁灭性的。在这些情况下，锥体死亡的原因尚不清楚。然而，由于视锥细胞损失可由非视锥细胞固有的事件引发，因此这些事件必须包括某种类型的细胞-细胞相互作用，可能包括分泌分子的作用。这样的过程可能易于通过应用药理学或基于细胞的疗法而中断。除了进行性疾病如视网膜色素变性，还有一种小鼠模型，细胞周期蛋白D1敲除（KO）小鼠，其中变性被阻止。PR死亡的原因，以及逮捕的原因，都是未知的。这个模型可以提供一些关于如何在进行性疾病中阻止变性的见解。我们正在寻求使用视网膜微阵列来定义伴随小鼠PR死亡的基因表达变化，重点是导致视锥细胞死亡的事件。此外，我们将描述伴随细胞周期蛋白D1突变体中PR变性的停滞的基因表达变化。我们计划进一步研究这些基因在正常和病理组织中的表达模式。最后，我们将在小鼠中使用遗传方法探索其中一些基因的功能。

DESCRIPTION (provided by applicant): Many diseases that ultimately lead to blindness are caused by the degeneration of photoreceptor (PR) cells. Cones typically die after rods, with kinetics somewhat dependent upon the particular disease. Rod loss followed by cone loss is also seen in cases where a genetic etiology has not been established, as in some forms of macular degeneration. While humans are able to function quite well without rods, the loss of cone-mediated vision is devastating. The reason(s) that cones die in these cases is unknown. However, since cone loss can be initiated by events that are not intrinsic to cones, these events must include some type of cell-cell interaction, perhaps including the action of a secreted molecule(s). Such a process may be susceptible to interruption through the application of a pharmacological or a cell based therapy. In addition to progressive diseases such as retinitis pigmentosa, there is a mouse model, the cyclin D1 knock-out (KO) mouse, in which degeneration is arrested. The cause of PR death, as well the cause of the arrest, are unknown. This model may provide some insight into how degeneration can be arrested in progressive diseases. We are seeking to use retinal microarrays to define the gene expression changes that accompany PR death in mice, with an emphasis on the events that lead to cone death. In addition, we will characterize the gene expression changes that accompany the arrest of PR degeneration in the cyclin D1 mutant. We further plan to characterize the expression patterns of such genes in normal and pathological tissue. Finally, we will explore the function of some of these genes using genetic approaches in mice.