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Principal Investigator: Alex J. Vecchio
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $159,785
Funding agency: National Institute of General Medical Sciences
Project Summary
Tight junctions (TJs) at the boundaries of endothelial and epithelial cells are critical in the development and
function of vertebrates because they enable these tissues to separate, protect, and shape external epidermis
and limbs and internal organs and glands. TJs regulate molecular transport through the spaces between
individual cells (paracellular) while adhering cellular sheets. TJs perform two vital functions in tissues: 1) form
barriers to restrict paracellular flux of small molecules, protecting organisms from the external environment and
separating internal body compartments; and 2) creating size- and charge-selective pores, allowing permeability
of ions that maintain electrochemical gradients. Numerous proteins amass at TJs to form the macromolecular
assemblies necessary for barrier and pore function. But two families of membrane proteins—claudins and
TAMPs (TJ-associated Marvel proteins)—predominate TJ assembly, architecture, and function. As these TJ
integral membrane proteins (TJIMPs) are the sole components to span intracellular, intramembraneous, and
extracellular space, they act as cytoskeletal scaffolds and assemble side-by-side within a membrane (cis) and
with TJIMPs from adjacent cell membranes (trans) to form barriers and pores. The molecular structure of TJs
is dynamic. Changes in protein composition, interaction, conformation, or modification—useful for assembling
TJs to precisely tune paracellular transport under normal conditions—can also be mis-assembled, resulting in
pathologies such as cancer, Alzheimer’s, Parkinson’s, Huntington’s, ALS, stroke, food poisoning and
inflammatory bowel disease, renal wasting, hepatitis, and diseases of the skin, eyes, and ears. Molecular level
insights into TJ structure and dynamics; the mechanisms of assembly that govern barrier and pore function;
and how disabling these mechanisms leads to pathologies, remain unresolved matters in our fundamental
understanding of TJs. We propose here a comprehensive research program that uses highly interdisciplinary
approaches to determine structure–interaction–function relationships between TJIMPs at dynamic TJ
microenvironments. These approaches integrate structural biology of TJIMPs and their complexes with
information obtained by traditional and state-of-the-art bioinformatics, biochemical, biophysical, and functional
experiments. The research program intends to resolve the underlying molecular principles of TJ assembly and
disassembly by confronting technical challenges and, in the near-term, by answering specific questions on
TJIMP interaction networks, the basis of gut barrier breakdown by a bacterial toxin, and the mechanisms of
TJIMP form and function at the blood-brain barrier. The long-term goal of our laboratory is to elucidate the
molecular bases for construction, destruction, and reconstruction of TJs, occurring both naturally or via
disease-causing mechanisms, and to use the achieved insights to advance design and development of novel
therapeutics to remedy TJ-related ailments.
Terms: <AD dementia><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Apoplexy><Architecture><Bacterial Toxins><Bio-Informatics><Biochemical><Bioinformatics><Biophysics><Blood - brain barrier anatomy><Blood-Brain Barrier><Body Tissues><Brain Vascular Accident><Cancers><Cell Adhesion><Cell Body><Cell membrane><Cells><Cellular Adhesion><Cellular Matrix><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Charge><Complex><Cutaneous Disorder><Cytoplasmic Membrane><Cytoskeletal System><Cytoskeleton><Dermatoses><Development><Disabling><Disease><Disorder><Dysfunction><Ear Diseases><Endothelial Cells><Endothelium><Engineering / Architecture><Environment><Epidermis><Epithelial Cells><Epithelium><Extracellular Space><Extremities><Eye diseases><Family><Food Poisoning><Functional disorder><Gland><Goals><Hemato-Encephalic Barrier><Hepatitis><Human><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><Individual><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Integral Membrane Protein><Intercellular Space><Intrinsic Membrane Protein><Ions><Kidney><Kidney Urinary System><Knowledge><Laboratories><Limb structure><Limbs><Link><Macromolecular Structure><Malignant Neoplasms><Malignant Tumor><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Modern Man><Modification><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Molecular Structure><Molecular Transport><Non-Trunk><Occluding Junctions><Organ><Organism><Paralysis Agitans><Parkinson><Parkinson Disease><Pathology><Permeability><Physiopathology><Plasma Membrane><Primary Parkinsonism><Primary Senile Degenerative Dementia><Protein Family><Proteins><Research><Shapes><Side><Skin Diseases><Skin Diseases and Manifestations><Stroke><Structure><Surface Proteins><Tight Junctions><Tissues><Transmembrane Protein><Transmembrane Protein Gene><Transport Process><Vertebrate Animals><Vertebrates><Zonula Occludens><base><bases><biophysical foundation><biophysical principles><biophysical sciences><bloodbrain barrier><brain attack><cerebral vascular accident><cerebrovascular accident><conformation><conformational><conformational state><conformationally><conformations><cutaneous disease><dermal disease><dermal disorder><design><designing><developmental><ear disorder><experiment><experimental research><experimental study><experiments><eye disorder><inflammatory disease of the intestine><inflammatory disorder of the intestine><insight><interdisciplinary approach><intestinal autoinflammation><intracellular skeleton><living system><macromolecular assembly><malignancy><membrane assembly><membrane structure><multidisciplinary approach><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ocular disease><ocular disorder><ophthalmopathy><pathophysiology><plasmalemma><primary degenerative dementia><programs><reconstruction><renal><scaffold><scaffolding><senile dementia of the Alzheimer type><skin disorder><small molecule><stroked><strokes><structural biology><vertebrata><wasting>