The role of RB in the retina & other tissues

描述(申请人提供)：视网膜母细胞瘤蛋白(RB)对抑制视网膜、视网膜色素上皮、晶状体和其他眼组织中的癌症、调节细胞增殖和抑制细胞死亡至关重要。我们研究的长期目标是了解RB在眼睛健康和疾病中的重要性，这可能使我们能够开发治疗眼病的新疗法。Rb通过与E2F转录因子相互作用定位于基因启动子，并通过组装多聚染色质重塑复合体来调节基因表达。Rb本身受两个关键的磷酸化事件的调节：C端的磷酸化阻断了Rb抑制细胞增殖的能力，而丝氨酸-567处额外的Rb磷酸化阻止了Rb抑制细胞死亡的能力。同时，我们发现Rb对眼部黑素细胞的分化和存活至关重要，黑素细胞是一种色素细胞，在眼部黑色素瘤、白化病、小眼炎和其他眼部疾病的发病机制中发挥着重要作用。当RB被最低限度的磷酸化时，它处于最活跃的形式，并能够与小眼球转录因子(MITF)合作，诱导黑素细胞分化和停止增殖。当Rb部分磷酸化时，它失去了抑制细胞增殖的能力，但仍然阻止了细胞死亡。当Rb被丝氨酸-567的磷酸化完全失活时，它不再能阻止细胞死亡。适当地，丝氨酸-567的磷酸化只发生在异常细胞中。我们推测，RB根据其磷酸化状态对细胞增殖和细胞死亡的单独调控，在正常细胞增殖过程中作为一种缓冲，防止细胞意外死亡，同时为消除可能导致癌症和其他疾病的异常细胞提供了一种机制。利用我们的眼部黑素细胞模型，我们围绕三个特定目标组织了一系列实验，以确定RB如何调节眼部黑素细胞的细胞增殖、分化和细胞死亡。了解RB是如何完成这些功能的，可能会导致新的治疗方法来消除癌细胞，或者防止正常细胞的损失，并鼓励黄斑变性和视网膜色素变性等眼病的组织再生。因此，这些目标与NEI的愿景声明高度相关，它们涉及视网膜疾病计划的几个主要计划目标和目标。

DESCRIPTION (provided by applicant): The retinoblastoma protein (Rb) is critical for suppressing cancer, regulating cell proliferation, and inhibiting cell death in the retina, retinal pigment epithelium, lens and other ocular tissues. The long-term goal of our research is to understand the importance of Rb in ocular health and disease, which may allow us to develop new therapies for eye disorders. Rb localizes to gene promoters through its interaction with E2F transcription factors, and it regulates gene expression by assembling multimeric chromatin remodeling complexes. Rb itself is regulated by two key phosphorylation events: phosphorylation of the C-terminus blocks the ability of Rb to inhibit cell proliferation, whereas additional phosphorylation of Rb at serine-567 blocks the ability of Rb to inhibit cell death. Concurrently, we have shown that Rb is critical for the differentiation and survival of ocular melanocytes - a type of pigment cell that plays an important role in the pathogenesis of ocular melanoma, albinism, microphthalmia and other eye diseases. When Rb is minimally phosphorylated, it is in its most active form and is able to cooperate with the microphthalmia transcription factor (MITF) to induce melanocytes to differentiate and cease proliferating. When Rb becomes partially phosphorylated, it looses the ability to inhibit cell proliferation but it still blocks cell death. When Rb is completely inactivated by phosphorylation of serine-567, it can no longer prevent cell death. Appropriately, serine-567 phosphorylation occurs only in abnormal cells. We hypothesize that the separate regulation of cell proliferation and cell death by Rb according to its phosphorylation state serves as a buffer against inadvertent cell death during normal cell proliferation while providing a mechanism for eliminating abnormal cells that could lead to cancer and other diseases. Using our ocular melanocyte model, we propose a series of experiments organized around three specific aims to determine how Rb regulates cell proliferation, differentiation and cell death in ocular melanocytes. Understanding how Rb accomplishes these functions could result in new treatments to eliminate cancer cells and alternatively, to prevent the loss of normal cells and encourage tissue regeneration in eye diseases such as macular degeneration and retinitis pigmentosa. Consequently, these aims are highly relevant to the vision statement of the NEI, and they address several major program goals and objectives of the Retinal Diseases Program.