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.

此申请是为竞争性更新的SRCS计划博士哈米德M。说 博士赛义德的计划侧重于研究：i）参与细胞/分子机制， 水溶性维生素（Vit.）的吸收/转运B1、B2、B3、B5、B6、B7、B 9和C）在 正常生理条件下的消化系统（小肠、结肠、胰腺）; ii） 这些过程如何在细胞、分子和遗传/表观遗传水平上受到调节; iii）如何 内部和外部/环境因素以及疾病状况影响这些过程， 缺陷;以及iv）所涉及的转运蛋白中的基因突变如何导致 这些转运蛋白的功能和系统性和/或局部（组织特异性） 缺陷水溶性维生素是正常人体健康和良好的必需微量营养素- 存在，以及它们的缺陷（无论是系统性的还是局部的）导致了许多严重的临床 从贫血到神经系统、心血管和皮肤病的异常 以及生长迟缓等等。不足/次优水平的发生率 水溶性维生素在退伍军人和普通人群中很常见， 由于各种原因/条件发生，包括慢性饮酒，慢性 暴露于香烟烟雾，肠道疾病（炎性肠病，乳糜泻， 肠切除术），食源性肠道病原体感染，糖尿病，药物营养 相互作用和老化。我们的计划利用最先进的方法来实现我们的目标。这 包括使用组织特异性和整体敲除动物模型，分离 细胞/膜/细胞器、人类初级肠道和结肠、高级分子和 共焦成像技术等。我们在全球领先，拥有260多个原创 同行评审和原创研究文章（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载体介导的过程，运输许多 在上述水溶性维生素中，确定/表征转运系统 涉及，描述如何表达和这些转运蛋白的功能是调节在 转录/转录后/翻译后水平，研究他们的细胞生物学方面， 以适当的细胞/细胞器膜域为目标，它们是如何被贩运的 以及这些事件如何受到遗传临床突变的影响。我们还开创了 关于外生/环境因素影响的工作（e.例如，在一个实施例中，慢性酒精暴露，肠道 病原体和细菌毒素，药物-维生素相互作用，长期暴露于香烟烟雾） 这些微量营养素的吸收和运输以及内部因素（例如，例如，在一个实施例中，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 描述在人体中存在有效和特异性的载体介导的摄取过程 结肠吸收了许多微生物群产生的水维生素。另一个关键特征 我们的计划一直是我们与地方和国家VA建立的合作， 大学调查人员以及许多小学生的指导/培训。高级细胞研究者 分子生理学和病理生理学。我们的项目一直得到 35年来多次获得VA和NIH奖项。本申请旨在强调 我们的计划取得成功，并要求SRCS奖续期，以便我们能够继续我们的 我们将继续努力，不断取得新的成功，并指导新一代的调查人员。