BLRD Research Career Scientist Award Application

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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.