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Principal Investigator: Zhenyu Zhong
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2021
Award: $410,000
Funding agency: National Institute of General Medical Sciences
Project Summary
A balanced supply of deoxynucleoside triphosphates (dNTPs), the building blocks for DNA, is vital for the
synthesis or repair of both nuclear and mitochondrial genomes, whereas its imbalance results in genome
instability that precipitates cellular damage and breach of homeostasis. Research on dNTP metabolism has
been traditionally conducted in highly proliferative (e.g. tumor cells), metabolically active (e.g. muscle cells) or
virus-infected cells due to the key roles of dNTPs in fulfilling demands for cell growth, energy production and
viral replication. However, little is known regarding the role of dNTP metabolism in innate immunity, especially
in the context of nonpathogen-induced immune activation. A hallmark of innate immune activation is the
assembly of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome—a dominant innate
immune sensor for tissue damage. The NLRP3 inflammasome is composed of the sensor NLRP3, the adaptor
ASC (apoptosis associated spike-like protein) and the effector pro-caspase-1. Assembly of the NLRP3
inflammasome proceeds with two distinct steps: ‘priming’ and ‘activation’. Priming entails rapid NF-kB
activation for initiating de novo synthesis of pro-IL-1β as well as increasing the amount of NLRP3. In contrast,
activation involves the assembly of the NLRP3 inflammasome machinery, resulting in autocleavage and
activation of caspase-1 which then converts immature pro-IL-1β into bioactive IL-1β—a powerful
proinflammatory cytokine that ignites inflammation. Although properly controlled NLRP3 inflammasome activity
allows for restoration of homeostasis after traumatic tissue injury by stimulating damage clearance and tissue
repair, its aberrant and prolonged activation also promotes the rapid progression of many devastating
disorders, including gouty arthritis, Alzheimer’s disease, atherosclerosis, macular degeneration and cancer. It
is therefore crucial to understand how NLRP3 inflammasome activity is regulated in innate immune cells.
Recently, we discovered that genetic deletion of CMPK2 or SAMHD1, two key enzymes within the dNTP
metabolic pathways responsible for synthesizing or degrading dNTPs respectively, orchestrates NLRP3
inflammasome activation. Therefore, the ultimate goal of this MIRA R35 project is to establish dNTP
metabolism as a new layer for innate immune regulation and further delineate its underlying mechanism of
action. To achieve this goal, three major scientific questions will be pursued: (1) how does inflammasome
priming regulate the function of dNTP metabolic enzymes? (2) how does dNTP metabolism control NLRP3
inflammasome activation? Lastly, since NLRP3 inflammasome overactivation is a shared pathogenic hallmark
of many diseases, we further asked: (3) do common disease risk factors, such as aging and obesity,
dysregulate macrophage dNTP metabolism, thereby permitting NLRP3 inflammasome overactivation?
Completion of this project will not only fill an important knowledge gap in the innate immunity field, but may
also guide new therapy development to prevent NLRP3 inflammasome hyperactivation.
Terms: <AD dementia><Affect><Aging><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 1><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autoregulation><Beta Proprotein Interleukin 1><Body Tissues><CASP-1><CASP1><CASP1 gene><Cancers><Caspase-1><Caspase-1 Gene><Cell Body><Cells><Cellular Expansion><Cellular Growth><Cellular injury><DNA><Deoxyribonucleic Acid><Disease><Disorder><Enzyme Gene><Enzymes><Genetic><Genome Instability><Genomic Instability><Goals><Gouty Arthritis><Homeostasis><ICE Protease><IL-1 beta><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1 β><IL-1-b><IL-1BC><IL-1b Converting Enzyme><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1B-Convertase><IL1BC><IL1BCE><IL1F2><IL1β><Immune><Immune Cell Activation><Immunes><Immunoglobulin Enhancer-Binding Protein><Immunomodulation><Inflammasome><Inflammation><Innate Immunity><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin 1beta><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Interleukin-1 beta><Interleukin-1β><Intermediary Metabolism><Knowledge><MEFV gene product><Macular degeneration><Macular degenerative disease><Malignant Neoplasms><Malignant Tumor><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Muscle Cells><Myocytes><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nuclear><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Obesity><Pathogenicity><Physiological Homeostasis><Preinterleukin 1 Beta><Primary Senile Degenerative Dementia><Production><Programmed Cell Death><Proteins><Receptor Protein><Research><Risk Factors><Role><Tissues><Transcription Factor NF-kB><Tumor Cell><Virus><Virus Replication><adiposity><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><cell damage><cell growth><cell injury><cellular damage><corpulence><cytokine><damage to cells><dementia of the Alzheimer type><develop therapy><disease risk><disorder risk><fitness><immune activation><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><injury to cells><injury to tissue><intervention development><kappa B Enhancer Binding Protein><macrophage><malignancy><marenostrin><mitochondrial genome><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><nuclear factor kappa beta><prevent><preventing><primary degenerative dementia><pyrin><receptor><repair><repaired><restoration><senile dementia of the Alzheimer type><sensor><social role><therapy development><tissue injury><tissue repair><treatment development><triphosphate><tripolyphosphate><viral multiplication><viral replication><virus multiplication>