Gene Expression Profiles of Retinal Degeneration

描述(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。球果通常在杆状之后死亡，动力学在某种程度上取决于特定的疾病。视杆细胞缺失后视锥细胞缺失也可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的情况下也能很好地运作，但视锥细胞介导的视力的丧失是毁灭性的。圆锥体在这些情况下死亡的原因(S)尚不清楚。然而，由于视锥细胞丢失可以由非视锥细胞固有的事件启动，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(S)。通过应用药物或基于细胞的治疗，这一过程可能容易受到干扰。除了进行性疾病，如视网膜色素变性，还有一种小鼠模型，即细胞周期蛋白D1基因敲除(KO)小鼠，其退化被阻止。PR的死亡原因以及逮捕的原因尚不清楚。这个模型可能会为如何在进展性疾病中阻止退化提供一些见解。我们正在寻求使用视网膜微阵列来定义小鼠PR死亡伴随的基因表达变化，重点是导致视锥细胞死亡的事件。此外，我们还将分析细胞周期蛋白D1突变体中伴随PR变性停止的基因表达变化。我们还计划进一步研究这些基因在正常组织和病理组织中的表达模式。最后，我们将使用遗传学方法在小鼠身上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.