New molecular paradigms for the molecular basis and prevention of Treacher Collins syndrome

项目摘要 先天性出生缺陷每年影响全世界700多万新生儿，三分之一与先天性缺陷有关。 颅面异常通常会导致严重畸形一个最极端的颅面 Treacher柯林斯综合征（TCS）是一种发育不良的下颌和脸颊 骨头最严重的TCS病例会导致婴儿死亡或严重的终身发病，这是由于一系列的 症状包括听力和视力丧失，进食和呼吸问题，以及大脑发育迟缓 发展目前还没有已知的治疗TCS的方法，症状只能在出生后通过 从婴儿期到成年期的全面多阶段手术重建。因为TCS治疗 很少能完全矫正，而且非常昂贵，因此显然需要开发产前治疗药物， 改善并可能预防TCS的方法。如果我们计划开发新的策略来预防TCS， 那么我们必须在最基本的分子水平上了解TCS。长期目标是 研究建议是建立一个坚实的基础，初步研究，以制定一个R01的建议，重点是 阐明TCS相关突变如何破坏Pol I转录过程的分子机制。 其基本原理是阐明TCS突变的分子机制将有助于我们更好地理解 Pol I和TCS失调之间的联系。我们假设TCS突变破坏了 Pol I相互作用网络中的分子相互作用，导致核糖体缺陷和疾病。到 为了验证这一点，我们提出了以下两个具体目标：1）确定TCS表型的遗传抑制因子， 酵母，将指导未来在更复杂的疾病模型中对这些潜在抑制因子的研究，以及2） 确定TCS突变如何破坏各种细胞类型中Pol I复合物的完整性，这将指导未来的研究 合适的疾病模型。为了实现这些目标，我们将使用跨学科的组合， 完善的和互补的分子遗传学，生物化学和生物物理学方法， 系统地表征和抑制TCS突变表型。拟议的研究意义重大 因为它将导致对TCS突变的分子基础的详细理解， 改变了目前调控面骨发育中rRNA合成的分子模式， 为预防性治疗指明了新的起点。

Project Summary Congenital birth defects affect more than 7 million births annually worldwide and one third are associated with craniofacial abnormalities that often result in severe deformities. One of the most extreme craniofacial disorders is Treacher Collins Syndrome (TCS), characterized by an underdeveloped lower jaw and cheek bones. The most severe TCS cases result in infant death or significant lifelong morbidity due to an array of symptoms that include loss of hearing and vision, problems with eating and breathing, and delayed brain development. There are no known cures for TCS, and symptoms can only be managed postnatal by a comprehensive multi-stage surgical reconstruction from infancy to adulthood. Because TCS treatments are seldom fully corrective and are exceedingly expensive, there is a clear need to develop prenatal therapeutic approaches to ameliorate and possibly prevent TCS. If we plan to develop novel strategies to prevent TCS, then it is essential that we understand TCS at its most basic molecular level. The long-term objective of this research proposal is to build a solid foundation of preliminary studies to develop an R01 proposal focused on elucidating the molecular mechanism of how TCS-associated mutations disrupt the Pol I transcription process. The rationale is that elucidating the molecular mechanism of TCS mutations will help us better understand the connection between dysregulated Pol I and TCS. We hypothesize that TCS-mutations disrupt essential molecular interactions within the Pol I interaction network that results in ribosome deficiency and disease. To test this, we propose the following two specific aims:1) Identify genetic suppressors of the TCS phenotype in yeast that will guide future studies of these potential suppressors in more complicated disease models, and 2) Determine how TCS mutations disrupt Pol I complex integrity in various cell types that will guide future studies on appropriate disease models. To accomplish these aims, we will use an interdisciplinary combination of well-established and complementary molecular genetic, biochemical, and biophysical approaches to systematically characterize and suppress TCS mutant phenotypes. The proposed research is significant because it will lead to a detailed understanding of the molecular basis of TCS mutations that has the potential to alter current molecular paradigms for the regulation of rRNA synthesis in facial bone development and may illuminate new starting points for preventative therapies.