Failure of vesicular transport and development of multi-organ defects through acidic melanosomal and lysosomal granules

通过酸性黑素体和溶酶体颗粒导致囊泡运输失败和多器官缺陷的发展

• 批准号: 16390319
• 负责人: JIMBOW Kowichi
• 金额: $ 9.15万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390319/
• 关键词: Melanin; Melanosome; Melanocyte; Transgene; GTP-binding protein; Pigmentation Disorder; Transgenic mouse; Rab7; トランスジーン; 低分子G蛋白; トランスジェニックマウス; Rab蛋白

This study characterizes the interrelationship between alteration of melanosome biosynthesis and functional failure of organs in man. The rationale behind this proposal is that there are marked similarities between melanosomes and lysosomes. This study characterizes the interrelationship between the biosynthesis of melanosomes and lysosomes and their functional roles in man. The rationale behind this proposal is that there exists a marked similarity in the biosynthesis processes between melanosomes and lysosomes, i.e., the two granules are present in acidic compartments and share many common biosynthesis processes such as vesicular transport from trans Golgi network (TGN). Melanosomes are made of glycoproteins, which consist of tyrosinase, tyrosinase-related proteins (TYRPs) and structural gp100 protein. Among these melanosomal proteins TYRP1 is the most abundant one. Our previous studies indicated (1) that the stage I melanosomes derive from endosomal granules such as early and late e … More ndosomes, (2) that melanosomal compartments are associated with cation independent-mannose 6 phosphate receptor (CI-M6PR) and regulated by ADP-ribosylation factor (ARF), and (3) that Rab7 (small GTP-binding protein) plays a key role in transport of TYRP1 from TGN to early melanosomes. In this project we wish to characterize the vesicular transport in the biosynthesis processes of acidic endosomal, lysosomal granules of melanosomes and their biological roles in man by utilizing transgenic mouse system.We found (1) that the inhibition of Rab7 function resulted in preferential TYRP1 elimination from melanocytes due to proteasomal degradation, (2) that endogenous and exogenous TYRP1 is co-immunoprecipitated with adaptin 1(AP1), (3) that the interaction between TYRP1 and AP1 is present in early stage of the TGN-derived vesicular transport, and (4) that Flag-tagged wt TYRP1 is co-localized with AP1, MGPR and GGA3. We also succeeded in establishing dominant/negative Rab7 transgenic mice, but are not yet successful in identifying visual pigmentation defects in these mice. Less

这项研究描述了人类黑素体生物合成的改变和器官功能衰竭之间的相互关系，其理论基础是黑素体和溶酶体之间存在显著的相似性。本研究描述了黑素体和溶酶体的生物合成及其在人体中的功能作用之间的相互关系。这一提议背后的基本原理是，黑素体和溶酶体之间的生物合成过程存在显著的相似性，即，这两种颗粒存在于酸性区室中，并且共享许多共同的生物合成过程，例如来自transGolgi网络（TGN）的囊泡转运。黑素体由糖蛋白组成，糖蛋白由酪氨酸酶、酪氨酸酶相关蛋白（TYRPs）和结构蛋白gp 100组成。在这些黑素体蛋白中，TYRP 1是最丰富的一种。我们以前的研究表明：（1）I期黑素体来源于内体颗粒，如早期和晚期黑素颗粒， ...更多信息 （2）黑素体区室与阳离子非依赖性甘露糖6磷酸受体（CI-M6 PR）相关并受ADP-核糖基化因子（ARF）调节;（3）Rab 7（小GTP结合蛋白）在TYRP 1从TGN转运到早期黑素体中起关键作用。本课题利用转基因小鼠系统研究了人黑素体酸性内体颗粒、溶酶体颗粒生物合成过程中的囊泡转运及其生物学作用，发现：（1）Rab 7功能的抑制导致TYRP 1通过蛋白酶体降解而优先从黑素细胞中清除;（2）内源性和外源性TYRP 1与适应蛋白1（AP 1）共沉淀;（3）TYRP 1与AP 1的相互作用存在于TGN囊泡转运的早期阶段;和（4）Flag标记的wt TYRP 1与AP 1、MGPR和GGA 3共定位。我们还成功地建立了显性/阴性Rab 7转基因小鼠，但尚未成功地确定这些小鼠的视觉色素沉着缺陷。少

项目成果

Rab7 interacts with the melanosomal matrix protein gp100/PMEL17/SILV and regulates its maturation in MMAC human melanoma cells

Rab7 与黑色素体基质蛋白 gp100/PMEL17/SILV 相互作用并调节其在 MMAC 人黑色素瘤细胞中的成熟

• 发表时间: 2006
• 期刊: Pigment Cell Res 19(5)
• 作者: Kawakami A;Sakane F;et al.
• 通讯作者: et al.

Mechanism of the immunosuppressive effect in vivo of novel immunosuppressive drug beta-SQAG9, which inhibits the response of the CD62L+ T-cell subset.

新型免疫抑制药物β-SQAG9抑制CD62L T细胞亚群反应的体内免疫抑制作用机制。

• 发表时间: 2005
• 期刊: Transplant Proc. 37(1)
• 作者: Takenouchi M;Sahara H;Yamamoto Y;Matsumoto Y;Imai A;Fujita T;Tamura Y;Takahashi N;Gasa S;Matsumoto K;Ohta K;Sugawara F;Sakaguchi K;Jimbow K;Sato N
• 通讯作者: Sato N

NPrCAP-magnetite with/without local heat generation can provide melanogenesis targeted drug delivery system, kill primarily inoculated melanoma by non-apoptosis and reject secondarily inoculated melanoma by HSP-mediated immune reaction.

具有/不具有局部发热的NPrCAP-磁铁矿可以提供黑色素生成靶向药物递送系统，通过非凋亡杀死初次接种的黑色素瘤，并通过HSP介导的免疫反应排斥二次接种的黑色素瘤。

• 发表时间: 2006
• 期刊: Melanoma Res 16(Suppl)
• 作者: Jimbow K;Takada T et al.
• 通讯作者: Takada T et al.

Rejection of secondly inoculated melanoma and prolongation of life span of melanoma-bearing mice by melanogenesis targeted chemo-thermo-immuno(CTI)therapy using NPrCAP-Magnetite nano-particles

使用 NPrCAP-磁铁矿纳米颗粒进行黑色素生成靶向化疗热免疫 (CTI) 治疗，拒绝二次接种黑色素瘤并延长黑色素瘤小鼠的寿命

• 发表时间: 2006
• 期刊: Pigment Cell Res 19(5)
• 作者: Takada T;Yamashita T et al.
• 通讯作者: Yamashita T et al.

Acquired multiple pilosebaceous cysts on the face having the histopathological features of statocystoma multiplex and eruptive vellus hair cysts.

面部获得多发性毛囊皮脂腺囊肿，具有多发性囊肿和发芽性毳毛囊肿的组织病理学特征。

• 发表时间: 2005
• 期刊: Int J Dermatol 44・10
• 作者: Yamada A;Jimbow K;et al.
• 通讯作者: et al.