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 effi...