BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10585365
• 负责人: HAMID M SAID
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2029-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585365
• 关键词: Address; Affect; Aging; Anemia; Animal Model; Animals; Area; Award; Bacterial Toxins; Biological; Biotin; Book Chapters; Books; Cardiovascular system; Carrier Proteins; Celiac Disease; Cell Line; Cell Separation; Cells; Cellular biology; Chronic; Chronic Disease; Clinical; Collaborations; Colon; Cultured Cells; DNA Sequence Alteration; Dermatologic; Development; Diabetes Mellitus; Diphosphates; Disease; Doctor of Philosophy; Educational process of instructing; Environmental Risk Factor; Epigenetic Process; Epithelium; Event; Excision; Exposure to; Folic Acid; Food-Drug Interactions; Functional disorder; Funding; General Population; Generations; Genetic; Genetic Transcription; Goals; Growth; Health; Height; Homeostasis; Human; Hypoxia; Imaging Techniques; Impairment; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intake; Intestinal Diseases; Intestines; Investigation; Large Intestine; Lead; Malabsorption Syndromes; Mediating; Medical Genetics; Membrane; Mentors; Micronutrients; Molecular; Molecular Biology; Mutation; Neurologic; Nicotinic Acids; Oral; Organ; Organelles; Pancreas; Pantothenic Acid; Peer Review; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Physiology; Post-Translational Regulation; Process; Publishing; Research; Research Personnel; Riboflavin; Scientist; Seminal; Small Intestines; Structure; System; Thiamine; Tissues; Training; Transport Process; United States National Institutes of Health; Universities; Veterans; Vitamin B6; Vitamins; Water; Water-Soluble Vitamin; Work; absorption; alcohol exposure; ascorbate; career; chronic alcohol ingestion; confocal imaging; cytokine; enteric pathogen; exposure to cigarette smoke; foodborne; gastrointestinal system; imaging approach; improved; interest; knockout animal; microbiota; molecular imaging; next generation; posttranscriptional; prevent; programs; success; trafficking; uptake

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.

此申请用于哈米德·赛义德 (Hamid M. Said) 博士的 SRCS 计划的竞争性更新。 Said 博士的项目重点研究：i) 参与的细胞/分子机制 水溶性维生素（维生素 B1、B2、B3、B5、B6、B7、B9 和 C）在器官中的吸收/运输 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/表观遗传水平上调节这些过程； 内部和外部/环境因素以及疾病状况影响这些过程，导致 缺陷；以及 iv) 相关转运蛋白的基因突变如何导致损伤 这些转运蛋白的功能以及系统性和/或局部性（组织特异性）的发育 水溶性维生素是人体正常健康所必需的微量营养素。 及其缺陷（无论是全身性的还是局部性的）导致了一系列严重的临床问题 异常范围从贫血到神经、心血管和皮肤疾病 以及生长迟缓等。缺乏/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人群中很常见，并且 由于多种原因/条件而发生，包括长期饮酒、慢性 接触香烟烟雾、肠道疾病（炎症性肠病、乳糜泻、 肠切除术）、食源性肠道病原体感染、糖尿病、药物营养 我们的计划利用最先进的方法来实现我们的目标。 包括使用组织特异性和整体敲除动物模型、分离的 细胞/膜/细胞器、人类初级肠类和类结肠、高级分子和 我们拥有 260 多项原创技术，在全球处于领先地位。 同行评审和原创研究文章（加上许多评论/书籍章节和书籍）。 他们是第一个发现特定载体介导的许多物质运输过程的存在的人 上述水溶性维生素的运输系统的识别/表征 涉及，描述这些转运蛋白的表达和功能是如何在 转录/转录后/翻译后水平，研究其细胞生物学 针对适当的细胞/细胞器膜域，它们如何被贩运 细胞内，以及这些事件如何受到基因临床突变的影响，我们也开创了先河。 关于外源/环境因素（例如，长期酒精暴露、肠道 病原体和细菌毒素、药物-维生素相互作用、长期接触香烟烟雾） 这些微量营养素以及内部因素（例如慢性病）的吸收和运输 我们也是第一个接触促炎细胞因子和病理生理性缺氧的人。 描述人类中有效且特定的载体介导的摄取过程的存在 结肠吸收许多微生物群产生的水维生素的另一个关键特征。 我们计划的重点是我们与地方和国家 VA 建立的合作， 大学研究人员，以及高级细胞领域许多初级研究人员的指导/培训 我们的项目一直受到以下机构的资助。 超过 35 年荣获多项 VA 和 NIH 奖项。当前的申请旨在突显该奖项。 我们的计划取得了成功，并请求续签 SRCS 奖项，以便我们能够继续我们的计划 迈向新的成功高度并指导新一代调查人员。