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（retinoblastoma protein, Rb）在视网膜、视网膜色素上皮、晶状体和其他眼部组织中对抑制肿瘤、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在眼部健康和疾病中的重要性，这可能使我们能够开发新的眼部疾病治疗方法。Rb通过与E2F转录因子的相互作用定位于基因启动子，并通过组装多聚体染色质重塑复合物调节基因表达。Rb本身受两个关键磷酸化事件的调控：c端磷酸化阻断Rb抑制细胞增殖的能力，而Rb丝氨酸-567位点的额外磷酸化阻断Rb抑制细胞死亡的能力。同时，我们已经证明Rb对眼部黑色素细胞的分化和存活至关重要，黑色素细胞是一种色素细胞，在眼部黑色素瘤、白化病、小眼症和其他眼部疾病的发病机制中起着重要作用。当Rb被最低限度磷酸化时，它处于最活跃的状态，能够与小眼转录因子（MITF）合作，诱导黑素细胞分化并停止增殖。当Rb部分磷酸化时，它失去了抑制细胞增殖的能力，但它仍然阻止细胞死亡。当Rb因丝氨酸-567磷酸化而完全失活时，它不再能阻止细胞死亡。丝氨酸-567磷酸化只发生在异常细胞中。我们假设Rb根据其磷酸化状态分别调控细胞增殖和细胞死亡，在正常细胞增殖过程中起到缓冲作用，防止细胞意外死亡，同时提供一种消除可能导致癌症和其他疾病的异常细胞的机制。利用我们的眼部黑素细胞模型，我们提出了一系列围绕三个特定目标组织的实验，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如何完成这些功能可能会导致新的治疗方法，以消除癌细胞，或者防止正常细胞的损失，并促进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，它们解决了视网膜疾病计划的几个主要计划目标和目的。

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.