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CASH--A NOVEL BHLH PROTEIN--ROLE IN GENE TRANSCRIPTION

CASH——一种新型 BHLH 蛋白质——在基因转录中的作用

基本信息

批准号：
2259743
负责人：
ANGELA R PORTA
金额：
$ 5.28万
依托单位：
ROCHE INSTITUTE OF MOLECULAR BIOLOGY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 1995-08-31
项目状态：
已结题

项目摘要

Proteins regulating gene transcription have been identified, characterized, and classified based on common structural motifs. One motif identified in a growing family of transcription factors is the basic helix-loop-helix (bHLH) domain. Proteins manifesting the BHLH domain participate in the regulation of cell specification and differentiation. For example proteins from the Drosophila achaete-scute complex, regulate neuronal development. A CDNA clone encoding a novel member of the BHLH protein superfamily homologous to these proteins has been isolated from a catfish (Ictalurus punctatus) olfactory epithelium CDNA library. This BHLH protein, named CASH (catfish achaete-acute homolog) is particularly interesting as olfactory epithelium contains neuronal precursors capable of continuous division and differentiation to form olfactory neurons. In light of the role that BHLH transcription factors play in the regulation of cell specification and differentiation, this proposal will study and characterize this BHLH protein and the role in plays in regulating gene expression. To achieve this we plan to; -determine the tissue and cell distribution of the CASH MRNA; express the CASH BHLH protein for antiserum production for immunocytochemical localization and functional studies; identify the DNA sequence motif to which the CASH BHLH protein binds; characterize homo- and heteromeric protein-protein interactions of the CASH protein; evaluate the role of post-translational modifications on the activities of this proteins; identify and characterize the genes that the CASH protein interacts with and evaluate how they are regulated; determine if there are other related BHLH proteins in olfactory mucosa of teleosts and other vertebrates. This will expand knowledge of the BHLH family of transcription factors and advance our understanding of the molecular basis by which these proteins regulate gene transcription. Detailed knowledge of BHLH proteins and the normal mechanisms by which they regulate gene transcription is critical in understanding how disturbances in gene transcription result in metabolic and degenerative diseases associated with aging, oncogenesis, and in response to trauma. This research, coupled with coursework in neuroscience and molecular biology, will upgrade the applicant's skills and serve as an essential bridge for her process and development as an independent investigator so that she may eventually obtain an academic position to pursue independent research studying gene regulation in the nervous system.

已经鉴定了调节基因转录的蛋白质，根据共同的结构基序进行表征和分类。一在不断增长的转录因子家族中鉴定出的基序是碱性螺旋-环-螺旋（bHLH）结构域。表现BHLH的蛋白质类结构域参与细胞特化的调节，分化例如果蝇的蛋白质复杂，调节神经元发育。一种编码新的与这些蛋白质同源的BHLH蛋白超家族的成员具有分离自鲶鱼（Ictalurus punctatus）的嗅上皮 CDNA文库这种BHLH蛋白，命名为CASH（鲶鱼achaete-acute 同源物）是特别有趣的，因为嗅觉上皮含有能够连续分裂和分化的神经元前体形成嗅觉神经元。鉴于BHLH转录在因子在细胞特化和分化的调节中起作用，这项提案将研究和表征这种BHLH蛋白及其作用，在调节基因表达中的作用。为了实现这一目标，我们计划： - 确定CASH mRNA的组织和细胞分布; CASH BHLH蛋白用于免疫细胞化学抗血清生产定位和功能研究;确定DNA序列基序， CASH BHLH蛋白质结合;表征同源和异聚 CASH蛋白的蛋白质-蛋白质相互作用;评估对这些蛋白活性的翻译后修饰; 鉴定和表征与CASH蛋白相互作用的基因并评估它们是如何被监管的;确定是否有其他相关的硬骨鱼和其他脊椎动物嗅粘膜中的BHLH蛋白。这将扩大BHLH家族转录因子的知识并推进我们对分子基础的理解，蛋白质调节基因转录。详细了解BHLH 蛋白质及其调节基因的正常机制转录对于理解基因干扰如何影响转录导致代谢和退行性疾病相关与衰老、肿瘤发生和创伤有关。这项研究，再加上神经科学和分子生物学的课程，提升申请人的技能，并作为她的重要桥梁作为一名独立的调查员，她可以最终获得学术地位，从事独立研究研究神经系统中的基因调控。