Albinism: Defects in Tyrosinase, Amines, or Melanin

白化病：酪氨酸酶、胺或黑色素缺陷

• 批准号: 6708851
• 负责人: SUZANNE Katherine ROFFLER-TARLOV
• 金额: $ 15.85万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708851
• 关键词: albinism; albino mouse; amines; biological signal transduction; cell differentiation; embryo /fetus cell /tissue; enzyme activity; enzyme deficiency; ganglion cell; gene expression; gene mutation; genetically modified animals; genotype; high performance liquid chromatography; immunocytochemistry; melanins; monophenol monooxygenase; neurogenesis; organ culture; pigments; polymerase chain reaction; retinal ganglion; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): This proposal requests funding for examination of the hypotheses that (1) tyrosinase activity in the embryonic eye results in the formation of developmental signals, that (2) these signals, perhaps amines, direct the generation of ganglion cells in the embryonic eye and that (3) the signals made through the activity of tyrosinase are transient and are made before tyrosinase switches to the synthesis of melanin in the pigment epithelium. The effects of amines on spatiotemporal features of neurogenesis would in turn lead to designation of the crossed and uncrossed projection of retinal ganglion cells. Our studies will focus on two lines of mice that are genetically identical except for a mutation at the tyrosinase locus. One line is pigmented (C57B16 Tyr+), the other, the albino (C57B16 Tyrc2j) carries a point mutation in the gene that codes for tyrosinase. The albino is known to have aberrant ganglion cell projections with the ipsilateral pathway reduced by half. Lack of functional tyrosinase in the albino is also correlated with changes in the timing of generation of retinal ganglion cells. Using histological and biochemical techniques, we will determine whether catechol or other amines are formed transiently in the developing eye, as is the case in peripheral tissues. We will test whether these substances are formed as a consequence of tyrosinase activity, again, as occurs in peripheral tissues. We will examine developing eye to see if there is a switch from the formation of developmental signals by tyrosinase to the formation of melanin, as also may be the case in peripheral tissues. We will correlate these events with the birth and differentiation of retinal ganglion cells. If we do find candidates for developmental signals for generation of retinal ganglion cells, we will test their effectiveness as signals in retina in vitro, and in vivo using tissues from albino mice including the OA1 knockout in which a G protein coupled receptor within melanosomes is mutated. Ultimately, if such signals deriving from tyrosinase-driven pathway unrelated to melanin production, are found, this research will open doors to therapeutic intervention in individuals carrying the OA1 gene.

描述（由申请人提供）：该提案要求资助检查以下假设：（1）胚胎眼中的酪氨酸酶活性导致发育信号的形成，（2）这些信号（可能是胺）指导神经节细胞的生成(3)通过酪氨酸酶的活性产生的信号是短暂的，并且是在酪氨酸酶转换为色素上皮中黑色素的合成之前产生的。胺对神经发生的时空特征的影响反过来会导致视网膜神经节细胞的交叉和非交叉投影的指定。 我们的研究将集中于除了酪氨酸酶基因座突变之外基因相同的两个小鼠品系。一个系有色素（C57B16 Tyr+），另一系白化系（C57B16 Tyrc2j）在编码酪氨酸酶的基因中携带点突变。已知白化病患者的神经节细胞投射异常，同侧通路减少了一半。白化病患者缺乏功能性酪氨酸酶也与视网膜神经节细胞生成时间的变化有关。 利用组织学和生化技术，我们将确定儿茶酚或其他胺是否在发育中的眼睛中短暂形成，就像在周围组织中的情况一样。我们将再次测试这些物质是否是由酪氨酸酶活性形成的，就像在外周组织中发生的那样。我们将检查发育中的眼睛，看看是否存在从酪氨酸酶形成发育信号到黑色素形成的转变，外周组织也可能出现这种情况。我们将把这些事件与视网膜神经节细胞的诞生和分化联系起来。如果我们确实找到了生成视网膜神经节细胞的发育信号的候选者，我们将在体外测试它们作为视网膜信号的有效性，并使用白化小鼠的组织进行体内测试，包括OA1敲除，其中黑素体中的G蛋白偶联受体发生突变。最终，如果发现这些源自与黑色素产生无关的酪氨酸酶驱动途径的信号，这项研究将为携带 OA1 基因的个体的治疗干预打开大门。