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Principal Investigator: Gabrielle Entrup
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $24,847
Funding agency: National Heart Lung and Blood Institute
Project Abstract
Obesity is a major global public health concern. Worldwide, 39% of the population is overweight and 13% of the
population is obese. Obesity contributes to many other diseases, such as heart disease, stroke, some cancers,
and notably, type 2 diabetes (T2D). Currently, 425 million people globally have been diagnosed with T2D and
this number is expected to grow to over 600 million people by 2050. Although T2D itself is a non-communicable
disease, many patients with diabetes are more susceptible to microbial infections and exhibit a higher burden of
disease. Although obese animals have an increased production of myeloid cells, previous work from our labs
has shown that a failure to heal diabetic wounds corresponds to elevated levels of prostaglandin E2 (PGE2) in
the inflammatory macrophages that are recruited to the wound. Furthermore, past studies from our lab have
demonstrated that PGE2 signaling can impair the innate immune functions of macrophages. Therefore, we
hypothesized that diabetic obese mice would be more susceptible to a respiratory Pseudomonas aeruginosa
strain PA01 infection due to impaired function of lung resident and recruited macrophages. Preliminary studies
demonstrate that obese diabetic mice do have an increased P. aeruginosa burden in the lung 24 hours after
infection. Additionally, we have determined that naïve obese diabetic mice have an increase in lung neutrophils
compared to lean mice, however, after infection with P. aeruginosa, these mice have a decrease in neutrophils
compared to lean mice. This suggests that obese mice have a defect in neutrophil recruitment during infection.
Additionally, neutrophil function assays show that neutrophils from obese diabetic mice have a defect in killing
P. aeruginosa. These observations drive this proposal which will test the hypothesis that obese diabetic mice
have not only a defect in innate immune cell recruitment, but also a defect in innate immune cell function during
bacterial pneumonia. This hypothesis will be tested through two specific aims: Aim 1) determine the functional
defects in alveolar macrophages during P. aeruginosa infection and Aim 2) determine the bacterial clearance
and recruitment defects in neutrophils during P. aeruginosa infection. Throughout these aims, we explore sex
as a biological variable, as males have enhanced obesity-induced inflammation compared to females.
Experiments for these aims will be completed with the use of a murine diet induced obesity model, cells derived
from these mice, and human cells derived from discarded blood samples from patients with and without T2D.
The results from these innovative studies may inform treatments to improve outcomes from bacterial pneumonia
in patients with T2D. Completion of this proposal will also allow for the applicant to receive rigorous training in
experimental design, implementation, and interpretation that will help her become a successful, independent
scientist.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Adipose tissue><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Affect><Airway infections><Alveolar Macrophages><Animals><Anti-Bacterial Agents><Anti-Bacterial Response><Antibacterial Response><Apoplexy><Assay><Bacteria><Bacterial Infections><Bacterial Pneumonia><Bioassay><Biological Assay><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain Vascular Accident><COVID-19 virus><COVID19 virus><Cancers><Cardiac Diseases><Cardiac Disorders><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemotactic Cytokines><Chronic><Clinical><CoV-2><CoV2><Complication><Data><Defect><Diabetes Mellitus><Diabetic mouse><Diagnosis><Dinoprostone><Disease><Disorder><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Exhibits><Experimental Designs><Failure><Fatty Tissue><Female><Free Fatty Acids><Functional impairment><Gene Expression><Generations><Goals><Health><Heart Diseases><Hematopoietic><Homolog of Drosophila TOLL><Homologous Chemotactic Cytokines><Host Defense><Hour><Human><Immune><Immune response><Immune signaling><Immune system><Immunes><Immunological response><Immunomodulation><Impairment><Infection><Inflammation><Inflammatory><Insulin Resistance><Intercrines><Intermediary Metabolism><Intracellular Communication and Signaling><Ketosis-Resistant Diabetes Mellitus><Kinetics><Knowledge><Leanness><Link><Lung><Lung Respiratory System><Macrophage><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Maturity-Onset Diabetes Mellitus><Measures><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mononitrogen Monoxide><Morbidity><Morbidity - disease rate><Murine><Mus><Myeloid Cells><Mφ><NIDDM><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Nonesterified Fatty Acids><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obese Mice><Obesity><Organ><Over weight><Overweight><P aeruginosa><P aeruginosa associated pneumonia><P aeruginosa caused pneumonia><P aeruginosa induced pneumonia><P aeruginosa pneumonia><P aeruginosa-associated pneumonia><P aeruginosa-caused pneumonia><P aeruginosa-induced pneumonia><P. aeruginosa><P. aeruginosa associated pneumonia><P. aeruginosa caused pneumonia><P. aeruginosa induced pneumonia><P. aeruginosa infection><P. aeruginosa pneumonia><P. aeruginosa-associated pneumonia><P. aeruginosa-caused pneumonia><P. aeruginosa-induced pneumonia><PGE2><PGE2 alpha><PGE2alpha><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Persons><Phagocytes><Phagocytic Cell><Phagocytosis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Predisposition><Production><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Pseudomonas aeruginosa><Pseudomonas aeruginosa associated pneumonia><Pseudomonas aeruginosa caused pneumonia><Pseudomonas aeruginosa induced pneumonia><Pseudomonas aeruginosa infection><Pseudomonas aeruginosa pneumonia><Pseudomonas pyocyanea><Public Health><Publishing><Pulmonary Macrophages><RNA Seq><RNA sequencing><RNAseq><Regulation><Respiratory Infections><Respiratory Tract Infections><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Scientist><Sepsis><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skin Tissue><Slow-Onset Diabetes Mellitus><Spleen><Spleen Reticuloendothelial System><Stable Diabetes Mellitus><Stroke><Subcellular Process><Susceptibility><Symptoms><T2 DM><T2D><T2DM><TLR4><TLR4 gene><Testing><Thesaurismosis><Thinness><Tissues><Toll Homologue><Training><Transcription Alteration><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><adipose><adiposity><adult onset diabetes><adulthood><amebocyte><anti-bacterial><bacteria infection><bacteria pneumonia><bacterial disease><bactericidal><bactericide><biological sex as a modifier><biological signal transduction><blood infection><bloodstream infection><brain attack><burden of disease><burden of illness><cerebral vascular accident><cerebrovascular accident><chemoattractant cytokine><chemokine><coronavirus disease 2019 virus><coronavirus disease-19 virus><corpulence><cutaneous tissue><cytokine><diabetes><diabetes mouse model><diabetic><diabetic wound healing><diet-associated obesity><diet-induced obesity><diet-related obesity><differential expression><differentially expressed><disease burden><endothelial cell derived relaxing factor><experiment><experimental research><experimental study><experiments><hCoV19><heart disorder><hemopoietic><host response><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><improved outcome><infected with P. aeruginosa><infected with Pseudomonas aeruginosa><innate immune function><innovate><innovation><innovative><insight><insulin resistant><insulin tolerance><ketosis resistant diabetes><lung function><lung histology><male><malignancy><maturity onset diabetes><metabolism disorder><microbial><mortality><nCoV2><neoplasm/cancer><neutrophil><novel><ob/ob mouse><obese patients><oxidative damage><oxidative injury><patient oriented outcomes><patients with obesity><pulmonary><pulmonary function><pulmonary histology><recruit><respiratory><sex as a biological factor><sex as a biological measure><sex as a biological risk factor><sex as a biological variable><sex as a biological variance><sex as a biologically significant variable><sex as a fundamental variable><soft tissue><stem><stroked><strokes><tissue wound><toll-like receptor 4><transcriptional differences><transcriptome sequencing><transcriptomic sequencing><type 2 DM><type II DM><type two diabetes><viral infection><virus infection><virus-induced disease><white adipose tissue><wound><wounding><wounds><yellow adipose tissue>