Albinism: Defects in Tyrosinase, Amines, or Melanin

白化病：酪氨酸酶、胺或黑色素缺陷

• 批准号: 6860989
• 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/6860989
• 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）：该提案要求资金检查（（1）胚胎眼中酪氨酸酶活性的假设导致发育信号的形成，（（2）这些信号，也许是胺在胚胎中引导神经节细胞的产生上皮。胺对神经发生的时空特征的影响又导致指定视网膜神经节细胞的交叉和未划分的投影。 我们的研究将集中在两条小鼠上，除了酪氨酸酶基因座的突变外，它们在遗传上相同。一条线是有色的（C57B16 Tyr+），另一线是白化病（C57B16 Tyrc2J）的基因中的点突变，该突变代码为酪氨酸酶。众所周知，白化病具有异常的神经节细胞投影，同侧途径减少了一半。白化病中缺乏功能性酪氨酸酶也与视网膜神经节细胞产生时机的变化有关。 使用组织学和生化技术，我们将确定儿茶酚或其他胺在发育中的眼睛中是否瞬时形成，就像在外周组织中一样。我们将再次测试这些物质是否由于酪氨酸酶活性而形成，就像外周组织中发生的那样。我们将检查开发的眼睛，以查看是否从酪氨酸酶的发育信号形成到黑色素的形成，外周组织也可能是这种情况。我们将将这些事件与视网膜神经节细胞的出生和分化相关联。如果我们确实找到了用于产生视网膜神经节细胞的发育信号的候选者，我们将测试它们作为视网膜体外信号的有效性，并在体内使用来自白化小鼠的组织（包括OA1敲除），其中G蛋白偶联的受体在黑色素体内被突变。最终，如果发现从与黑色素产生无关的酪氨酸酶驱动的途径衍生出的这种信号，这项研究将为携带OA1基因的个体的治疗干预打开大门。

项目成果

Normalization of lens protein kinase Cgamma in galactosemic dogs by a novel aldose reductase inhibitor.

新型醛糖还原酶抑制剂使半乳糖血症犬晶状体蛋白激酶 Cgamma 正常化。

• DOI: 10.1111/j.1463-5224.2004.04016.x
• 发表时间: 2004
• 期刊: Veterinary ophthalmology.
• 作者: Takemoto,DoloresJ;Harris,Richard;Brightman,Al;McGill,John;Hua,Duy;Davidson,Harriet;Fenwick,Brad;Wagner,LynnM
• 通讯作者: Wagner,LynnM