ETHANOL EFFECTS ON VITAMIN TRANSPORT/MITOGENIC SIGNALING

乙醇对维生素运输/有丝分裂信号传导的影响

• 批准号: 3069343
• 负责人: GEORGE I HENDERSON
• 金额: $ 6.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-29 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3069343
• 关键词: affinity chromatography; alcoholic beverage consumption; alcoholism /alcohol abuse; apical membrane; autoradiography; basolateral membrane; binding proteins; biological signal transduction; cell growth regulation; embryo /fetus cell /tissue; embryo /fetus drug adverse effect; epidermal growth factor; fetal alcohol syndrome; gel electrophoresis; high performance liquid chromatography; human pregnant subject; human tissue; laboratory rat; liver cells; membrane activity; mitogens; mother /embryo /fetus nutrition; phosphorylation; placental transfer; prenatal growth disorder; thiamine; thin layer chromatography; tissue /cell culture; vitamin B6

The Candidate's immediate and long-term goals reflect a longstanding interest in the effects of ethanol on fetal growth and development. The "immediate" goal is to continue the ethanol related research which is presently funded and ongoing. The latter has evolved from previous work defining the impact of ethanol of fetal development. These essentially completed, more mechanistically oriented studies are now in progress. As should be the case, they have supplied, along with some answers, many question, especially regarding basic mechanisms of fetal cell mitogenic response. "Long-term" goals will b e to focus research on these ,but this will require a relatively stable faculty getting- tenure will be needed and a small (not absent) teaching load. The impacts of this award will be three-fold. First will be to replace the major "soft" money component of my salary, thereby allowing me to 1) continue working on the above projects for their duration and 2) obtain future grants related to these, as the Principal investigator, without salary constraints. Second, I am at a juncture in my career at which I must obtain tenure in order to continue at this institution. A five year salary commitment would greatly enhance the chances of this, allowing continuity of ongoing research. Third, the above salary commitment would release me from the additional teaching load required should further departmental monies be need for my support. Two related research approaches will utilized for the following studies. For the first, the overall goal is an improved understanding of the effects of ethanol on fetal nutrition by determining its effects on placental and fetal cell vitamin transport. Specific aims are 1) to establish the mechanisms of thiamine (B1) and vitamin B6 transport by the term human placenta, 2) to determine the effect of ethanol on these and 30 to undertake concomitant studies with fetal rat hepatocytes in culture. The second is to determine the mechanism(s) by which ethanol impairs fetal cell proliferation. More specifically, the means by which ethanol blocks the epidermal growth factor (EGF) mediated mitogenic responses in rat fetal hepatocytes will be probed. This will focus on the effect of ethanol on EGF receptor tyrosine kinase activity s the site of purturbation of replicative capacity. Inhibition of this process by ethanol may explain, at least in part, the adverse effects of in utero ethanol exposure on the fetus.

候选人的近期和长期目标反映了长期的目标 对乙醇对胎儿生长发育的影响感兴趣。这 “近期”目标是继续乙醇相关研究 目前已获得资助并正在进行中。后者是从以前的工作演变而来的 定义乙醇对胎儿发育的影响。这些本质上是 已完成，更多机械导向的研究正在进行中。作为 应该是这样，他们提供了许多答案以及一些答案 问题，特别是关于胎儿细胞有丝分裂的基本机制 回复。 “长期”目标将是集中研究这些，但这 需要相对稳定的教职人员获得——需要终身教职 教学负担小（并非不存在）。 该奖项的影响将是三重的。首先将是替换 我工资中主要的“软”钱部分，从而使我能够：1) 在上述项目期间继续开展工作，并且 2) 获得 作为首席研究员，与这些相关的未来资助，无需 薪资限制。其次，我正处于职业生涯的关键时刻。 必须获得终身教职才能继续在该机构工作。一个五年 薪资承诺将大大增加这种机会，允许 正在进行的研究的连续性。三、上述薪酬承诺 将我从所需的额外教学负担中解放出来应该进一步 我需要部门的资金来支持。 以下研究将采用两种相关的研究方法。 首先，总体目标是加深对 通过确定乙醇对胎儿营养的影响 胎盘和胎儿细胞维生素运输。具体目标是 1) 建立硫胺素 (B1) 和维生素 B6 转运机制 足月人胎盘，2) 确定乙醇对这些和的影响 30 开展与胎鼠肝细胞的伴随研究 文化。第二个是确定乙醇的作用机制 损害胎儿细胞增殖。更具体地说，采用的手段 乙醇阻断表皮生长因子（EGF）介导的有丝分裂 将探测大鼠胎儿肝细胞的反应。这将集中于 乙醇对 EGF 受体酪氨酸激酶活性的影响 复制能力的扰乱。通过以下方式抑制该过程 乙醇至少可以部分解释子宫内的不良影响 乙醇暴露对胎儿的影响。