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Principal Investigator: Vinitha Jacob
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $159,300
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY/ABSTRACT
Sepsis is a common and deadly disease and treatment options are limited to antibiotics and supportive care.
Endotoxemia is a key feature of sepsis pathogenesis and can also contribute to numerous other inflammatory
disorders. Growing antibiotic resistance and an aging population have contributed to an urgent unmet need for
new therapeutics for these conditions.
This K08 proposal will complete the training that will launch the independent career of Vinitha Jacob, MD,
PhD, a physician scientist in emergency medicine. She seeks to complement her expertise in zebrafish
development with additional training in mammalian systems to reach her long-term goal of developing both novel
and repurposed therapeutics for sepsis and other acute diseases.
In Dr. Jacob’s recently published work, she used the endotoxin lipopolysaccharide (LPS) to recapitulate key
features of sepsis pathogenesis. RNA sequencing (RNA-seq) identified cholesterol metabolism as one of the
most significantly altered pathways in LPS treated zebrafish and sepsis patients with poor outcomes.
Specifically, the mRNA for 7-dehydrocholesterol reductase (DHCR7), which catalyzes the conversion of 7-
dehydrocholesterol (7-DHC) to cholesterol, was significantly upregulated in LPS treated zebrafish and was one
of only two lipid-related gene associated with mortality in sepsis patients. Dr. Jacob made the novel finding that
fish treated with a DHCR7-specific inhibitor were completely protected from endotoxemic death. In her specific
aims, she will build on these findings and interrogate the mechanisms by which DHCR7 inhibition protects from
endotoxemia (Aim 1), test whether DHCR7 inhibition can also relieve LPS toxicity a mammalian model (Aim 2)
and identify clinically used DHCR7 inhibitors (Aim 3) that can be considered for repurposing for acute human
inflammatory diseases including sepsis.
These aims will elucidate the role of DHCR7 in endotoxemia and will identify clinically utilized DHCR7
inhibitors that mediate LPS toxicity. In completing the proposed aims under the guidance of established mentors
and leaders Dr. Shavit (genome editing), Dr. Dickson (mammalian endotoxemia/sepsis) and Dr. Schwendeman
(cholesterol metabolism), Dr. Jacob will complement her experience in zebrafish development with knowledge
in cholesterol metabolism and hands-on-training in genome editing techniques and mammalian models of
endotoxemia. The fertile training ground at the University of Michigan, with its strong history of developing
successful physician scientists, combined with an experienced mentorship team with relevant expertise will allow
Dr. Jacob to emerge from this career development award period as a uniquely trained emergency medicine
physician-scientist with expertise in both zebrafish and mammalian systems. She will thus have the ability take
her findings from initial discovery across the translational spectrum.
Terms: <7-DHC><7-dehydrocholesterol><7-dehydrocholesterol reductase><7-dehydrocholesterol-delta-7-reductase><AY 9944><AY9944><Acute><Acute Disease><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Award><Blood Vessels><Blood leukocyte><Brachydanio rerio><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Membrane Lipid Rafts><Cell membrane><Cells><Cessation of life><Cholesterol><Cholesterol Homeostasis><Clinical><Collaborations><Complement><Complement Proteins><Cytoplasmic Membrane><DHCR7 enzyme><Danio rerio><Data><Death><Death Rate><Dehydrocholesterols><Dehydrogenases><Development><Disease><Disorder><Doctor of Philosophy><Drug Utilization><Drugs><Emergency Medicine><Endotoxemia><Endotoxins><Enzyme Gene><Enzyme Inhibition><Enzymes><Extravasation><FDA approved><Fishes><Genes><Goals><History><Hospital Admission><Hospitalization><Human><Immune><Immune Cell Activation><Immune response><Immunes><Immunological response><In Vitro><Infection><Inflammation><Inflammatory><Inflammatory Response><K-Awards><K-Series Research Career Programs><Knowledge><Leakage><Leukocytes><Leukocytes Reticuloendothelial System><Libraries><Lipids><Lipopolysaccharides><Macrophage><Mammalia><Mammals><Marrow leukocyte><Mediating><Medication><Membrane><Membrane Microdomains><Mentors><Mentorship><Messenger RNA><Mice><Mice Mammals><Michigan><Miscellaneous Antibiotic><Modeling><Modern Man><Murine><Mus><Mφ><NADPH-sterol delta 7-reductase><Organ><Outcome><Oxidoreductase><Oxidoreductase Gene><Pathogenesis><Pathway interactions><Ph.D.><PhD><Pharmaceutical Preparations><Physicians><Plasma Membrane><Platelet aggregation><Publishing><RNA Seq><RNA sequencing><RNAseq><Recording of previous events><Reductases><Research Career Program><Resistance to antibiotics><Resistant to antibiotics><Role><Sampling><Scientist><Sepsis><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Spillage><Supportive Therapy><Supportive care><System><Techniques><Teratogenic><Teratogenicity><Teratogens><Testing><Therapeutic><Toxic effect><Toxicities><Training><Translating><Universities><Viral><White Blood Cells><White Cell><Work><Zebra Danio><Zebra Fish><Zebrafish><acute disease/disorder><acute disorder><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><antibiotic drug resistance><antibiotic resistant><blood infection><bloodstream infection><career><cholesterol metabolism><complementation><developmental><drug candidate><drug discovery><drug/agent><enzyme activity><experience><genome editing><genomic editing><histories><host response><immune activation><immune system response><immunoresponse><improved><in vivo><inflammatory modulation><inhibitor><lipid raft><mRNA><membrane structure><mortality><mortality rate><mortality ratio><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><plasmalemma><population aging><prevent><preventing><protective effect><sepsis patients><septic patients><social role><tool><transcriptome sequencing><transcriptomic sequencing><translational pipeline><translational spectrum><vascular><white blood cell><white blood corpuscle><zebrafish development>