BLRD Research Career Scientist Award Application

这份申请是为了竞争性地续签哈米德·M·赛义德博士的SRCS计划。 赛义德博士的计划侧重于研究：i)细胞/分子机制参与 水溶性维生素的吸收/转运(Vit.B1、B2、B3、B5、B6、B7、B9和C) 正常生理条件下的消化系统(小肠、结肠、胰腺)； 如何在细胞、分子和遗传/表观遗传水平上调控这些过程；三)如何 内部和外部/环境因素以及疾病状况影响这些过程 以及iv)所涉及的转运蛋白的基因突变如何导致 这些转运蛋白的功能和全身性和/或局限性(组织特异性)的发展 不足之处。水溶性维生素是人体正常健康和健康所必需的微量营养素。 以及它们的缺陷(无论是系统性的还是局部性的)导致了一系列严重的临床 从贫血到神经、心血管和皮肤病的各种异常 以及发育迟缓，以及许多其他问题。不足/次优水平的发生率 水溶性维生素在我们的退伍军人和普通民众中很常见，而且 发生于各种原因/状况，包括长期饮酒、慢性 接触香烟烟雾、肠道疾病(炎症性肠道疾病、乳糜泻、 肠道切除)，感染食源性肠道病原体，糖尿病，药物营养 相互作用和衰老。我们的计划利用最先进的方法来实现我们的目标。这 包括使用组织特定和全局基因敲除动物模型、分离的 细胞/膜/细胞器，人类初级肠样和结肠样体，高级分子和 共聚焦成像技术等。我们在全球领先，拥有260多个原创产品 同行评议和原创研究文章(加上许多评论/书籍章节和书籍)。我们 是第一个确定存在特定的承运人中介的运输过程的人 在上面提到的水溶性维生素中，识别/描述运输系统 描述了这些转运蛋白的表达和功能是如何在 Transcriptional/post-transcriptional/post-translational水平，研究它们的细胞生物学关于 针对适当的细胞/细胞器膜结构域，它们是如何被运输的 细胞内，以及这些事件如何受到基因临床突变的影响。我们还开创了 关于外源性/环境因素的影响的工作(例如，慢性酒精暴露、肠道感染 病原体和细菌毒素、药物-维生素相互作用、长期暴露在香烟烟雾中) 这些微量营养素的吸收和运输以及内部因素(如慢性 暴露于促炎细胞因子和病理生理缺氧)。我们也是第一个 描述人类体内存在有效和特定的载体介导的摄取过程 结肠为吸收许多微生物群产生的水分维生素。另一个关键特征 我们计划的一部分是我们与当地和国家VAS建立的合作 大学调查人员，以及许多JR.先进细胞领域的研究人员 以及分子生理学和病理生理学。我们的项目一直由 超过35年来多次荣获退伍军人事务部和美国国立卫生研究院奖。此当前应用程序旨在突出显示 并要求续签SRCS奖，以便我们可以继续我们的 向成功的新高度迈进，并指导新一代调查人员。

This application is for a competitive renewal of the SRCS program of Dr. Hamid M. Said. Dr. Said’s program focuses on studying: i) cellular/molecular mechanisms involved in the absorption/transport of water-soluble vitamins (Vit. B1, B2, B3, B5, B6, B7, B9 and C) in organ of the digestive system (small intestine, colon, pancreas) under normal physiological conditions; ii) how these processes are regulated at the cellular, molecular and genetic/epigenetic levels; iii) how internal and external/environmental factors and disease conditions affect these processes leading to deficiencies; and iv) how genetic mutations in the transporters involved lead to impairment in the function of these transporters and development of systemic and/or localized (tissue-specific) deficiencies. Water-soluble vitamins are essential micronutrients for normal human health and well- being, and their deficiencies (whether systemic or localized) lead to a host of serious clinical abnormalities that range from anemia to neurological, cardiovascular and dermatological disorders as well as growth retardation, among many others. The incidences of deficiency/sub-optimal levels of water-soluble vitamins are common in our Veterans as well as in the general population, and occur due to a variety of causes/conditions including chronic alcohol consumption, chronic exposure to cigarette smoke, intestinal diseases (inflammatory bowel diseases, celiac disease, intestinal resection), infection with foodborne enteric-pathogens, diabetes mellitus, drug-nutrient interactions, and aging. Our program utilizes state-of-the-art approaches to address our aims. This include using tissue-specific and global knockout animal models, isolated cells/membranes/organelles, human primary enteroids and colonoids, advanced molecular and confocal imaging techniques, among others. We have led the field globally with over 260 original peer-reviewed and original research articles (plus many reviews/book chapters and books). We were the first to identify the existence of specific carrier-mediated processes for transport of many of the water-soluble vitamins mentioned above, identify/characterize the transport systems involved, delineate how expression and function of these transporters are regulated at the transcriptional/post-transcriptional/post-translational levels, study their cell biology with regards to targeting to the appropriate cell/organelle membrane domains, how they are trafficked intracellularly, and how these events are affected by genetic clinical mutations. We also pioneered the work on effect of exogenous/environmental factors (e. g., chronic alcohol exposure, enteric pathogens and bacterial toxins, drug-vitamin interactions, chronic exposure to cigarette smoke) on absorption and transport of these micronutrients as well as that of internal factors (e. g., chronic exposure to pro-inflammatory cytokines and to pathophysiological hypoxia). We were also the first to describe the existence of efficient and specific carrier-mediated uptake processes in the human colon for the absorption of the many microbiota-generated water-vitamins. Another key hallmarks of our program has been the collaboration we have established with local and national VAs and university investigators, as well the mentoring/training of many Jr. investigators in advanced cell and molecular physiology and pathophysiology. Our program has been continuously funded by multiple VA and NIH awards for over 35 years. This current application is intended to highlight the success of our program and to request renewal of the SRCS award so that we can continue our progress towards new heights of successes as well as to mentor a new generation of investigators.