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光感受器（PR）细胞退化引起的。锥体通常在杆体之后死亡，其动力学多少取决于特定的疾病。在遗传病因尚未确定的情况下，如在某些形式的黄斑变性中，杆状体丢失后锥体丢失也可见。虽然人类在没有视杆细胞的情况下也能很好地工作，但失去视锥细胞介导的视力是毁灭性的。在这些情况下，锥体死亡的原因尚不清楚。然而，由于锥体损失可以由非锥体固有的事件引发，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。这一过程可能容易因药理学或细胞疗法的应用而中断。除了诸如视网膜色素变性等进行性疾病外，还有一种小鼠模型，即细胞周期蛋白D1敲除（KO）小鼠，其变性被阻止。PR的死亡原因和被捕原因都不得而知。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，重点是导致细胞死亡的事件。此外，我们将描述细胞周期蛋白D1突变体中PR变性停止的基因表达变化。我们进一步计划表征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.