HORMONE INDUCED EFFECTS ON GLYCOLIPID METABOLISM

这项研究的目的是了解生物化学和遗传学 影响鞘糖脂组织水平调节的因素 尤其是那些参与溶酶体膜组装和 了解在溶酶体结构中产生缺陷的遗传疾病。 人类疾病、切迪亚克-东氏综合征和赫尔曼斯基-普德拉克 综合征，是常染色体隐性遗传病中潜在的 生化缺陷还没有被发现。然而，这两种疾病 有溶酶体和黑素小体异常和血小板储存池 不足之处。因此，它们既是为了它们自己，也是为了它们自己 并有助于了解正常的溶酶体的形成和功能。一个 一系列小鼠色素沉着突变体已被鉴定为皮损 而功能缺陷类似于人类的紊乱，提供了一种独特的 有机会阐明所涉及的分子机制。每个人 的色素沉着突变体似乎有一个独特的主要遗传 影响溶酶体和其他的性质和组装的缺陷 细胞器膜。我们已经证明，溶酶体是在 雄激素对雄性和雌性大鼠肾脏近端小管细胞的影响 正常动物和突变动物中的小鼠。因为它的形态结构 睾酮诱导我们所拥有的每个突变体的溶酶体 似乎是独一无二的，看起来很可能每个突变体 溶酶体也可能有不同的异常膜成分 蛋白质或脂肪。的性质和新陈代谢的检查 正常和突变细胞中的膜成分可能导致 识别二次缺陷和可能的初级缺陷，并识别- 正常溶酶体膜所需成分的阳离子 集合。因此，我们将描述肾脏溶酶体的特征 来自正常和突变小鼠的膜成分；2)检查 正常和突变人特定溶酶体膜脂代谢的研究 培养中的肾细胞；3)睾酮反应特性 半乳糖基转移酶活性；4)遗传同源性试验 小鼠突变体与人类相关疾病；5)融合研究 正常和突变组织培养细胞的溶酶体与 布莱恩·斯托里博士。二次缺陷和一次缺陷的表征 影响溶酶体形态和功能的基因应该有助于 了解正常的溶酶体组装过程以及 这些遗传性溶酶体疾病的分子病理学。

The goals of this research are to understand the biochemical and genetic factors involved in the regulation of tissue levels of glycosphingolipids particularly those involved in the assembly of lysosomal membranes and to understand genetic disorders that produce defects in lysosome structure. The human diseases, Chediak-Higashi syndrome and Hermansky Pudlak syndrome, are autosomal recessive disorders in which the underlying biochemical defects have not been identified. However, both disorders have lysosome and melanosome abnormalities and platelet storage pool deficiencies. They are, therefore, of interest both for their own sake and as an aid in understanding normal lysosome formation and function. A series of mouse pigmentation mutants have been identified with lesions and functional defects similar to the human disorders and offer a unique opportunity for elucidation of the molecular mechanisms involved. Each of the pigmentation mutants appears to have a unique primary genetic defect that affects the properties and assembly of lysosomal and other organellar membranes. We have shown that lysosomes are induced in the proximal tubule cells of the kidney of male and androgen treated female mice in both normal and mutant animals. Because the morphology of the testosterone induced lysosomes of each of the mutants that we have examined appears unique, it seems probable that each of the mutant lysosomes could have a different abnormal membrane component, either protein or lipid. Examination of the nature and metabolism of the membrane components in normal and mutant cells could lead to identification of secondary and perhaps primary defects and to identifi- cation of components that are required for normal lysosomal membrane assembly. We therefore will 1) characterize the kidney lysosomal membrane components from normal and mutant mice; 2) examine the metabolism of specific lysosomal membrane lipids in normal and mutant kidney cells in culture; 3) characterize testosterone responsive galactosyltransferase activities; 4) test for genetic homology of the mouse mutants with the related human disorders; 5) study the fusion of lysosomes of normal and mutant tissue culture cells in collaboration with Dr. Brian Storrie. The characterization of secondary and primary defects that affect lysosomal morphology and function should contribute to understanding the normal lysosome assembly processes as well as the molecular pathology of these inherited lysosomal diseases.