HORMONE INDUCED EFFECTS ON GLYCOLIPID METABOLISM

这项研究的目标是了解生物化学和遗传学 参与调节组织鞘糖脂水平的因子 特别是参与溶酶体膜组装的那些， 了解导致溶酶体结构缺陷的遗传疾病。 人类疾病，Chediak-Higashi综合征和Hermansky Pudlak 综合征，是常染色体隐性遗传疾病，其中潜在的 尚未发现生化缺陷。 然而，这两种疾病 有溶酶体和黑素体异常和血小板储存池 缺陷 因此，它们本身也是有意义的， 并有助于理解正常溶酶体的形成和功能。 一 一系列的小鼠色素突变体已经被鉴定为病变 和功能缺陷类似的人类疾病，并提供了一个独特的 有机会阐明所涉及的分子机制。 每个 的色素沉着突变体似乎有一个独特的主要遗传 影响溶酶体和其他细胞的性质和组装的缺陷 细胞器膜 我们已经证明，溶酶体是在细胞中诱导的。 雄性和雄激素处理雌性的肾脏近端小管细胞 在正常和突变动物中的小鼠。 因为， 睾酮诱导的每个突变体的溶酶体， 经过检查，似乎是独一无二的，似乎每个突变体都有可能 溶酶体可能有不同的异常膜成分， 蛋白质或脂质。 检查药物的性质和代谢 正常和突变细胞中的膜成分可能导致 识别次要缺陷和可能的主要缺陷，并识别 正常溶酶体膜所需组分的阳离子 组装件. 因此，我们将1）表征肾脏溶酶体 正常和突变小鼠的膜组分; 2）检查 正常和突变体中特定溶酶体膜脂的代谢 培养的肾细胞; 3）表征睾酮响应性 半乳糖基转移酶活性; 4）测试的遗传同源性， 小鼠突变体与相关的人类疾病; 5）研究融合 正常和突变组织培养细胞的溶酶体与 博士布莱恩·斯托里 二次和一次缺陷的表征 影响溶酶体形态和功能的蛋白质 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.