Document text
Principal Investigator: Alexis M. Stranahan
Organization: AUGUSTA UNIVERSITY
Fiscal Year: 2024
Award: $392,018
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
The ‘apple-shaped’ anatomical pattern that accompanies visceral adiposity increases dementia risk in humans,
but the 'pear-shaped' distribution that reflects subcutaneous adiposity does not predict cognitive impairment and
may be protective. Several recent studies, including from our lab, have outlined signaling cascades linking
peripheral and central inflammation in obesity in males, but vulnerability to obesity-induced metabolic pathology
is sexually dimorphic, and susceptibility to neuroinflammation follows similar patterns. Adult females exhibit
stronger innate immunity, and evidence from clinical and experimental studies suggests that this dimorphism
involves sex differences in anti-inflammatory cytokines. However, current understanding of tissue-specific anti-
inflammatory signaling remains rudimentary due to the scarcity of approaches for selective manipulation.
Moreover, regionally heterogeneous responses to dietary obesity in different brain areas remain incompletely
characterized, leaving open questions surrounding feedforward neuroimmune control versus immunological
feedback. The proposed experiments will generate a comprehensive topographical map of neuroimmune
responses to chronic overnutrition and elucidate the role of the anti-inflammatory cytokine interleukin-4 in these
effects. We will use light-inducible cre drivers and direct delivery of tamoxifen metabolites to selectively
manipulate immune cells in cerebrospinal fluid. These technically innovative approaches will be followed by
anatomical mapping of lymphocytes and myeloid cells in cleared tissues, single-cell flow cytometric analysis, or
analysis of neuronal function at the behavioral and electrophysiological level. Understanding circuit-specific
sexual dimorphisms in obesity could yield fundamental insights into the pathogenesis of neuroinflammation in
different microenvironments, and could also identify target structures for noninvasive therapeutic modulation.
Terms: <4-Hydroxy-Tamoxifen><4-hydroxytamoxifen><4-monohydroxytamoxifen><AD dementia><Abbreviations><Abdominal obesity><Ablation><Adipose tissue><Adult females><Adult women><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amentia><Ammon Horn><Anatomic Sites><Anatomic structures><Anatomy><Android fat distribution><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apple><Area><Autocrine Systems><Autoimmune Diseases><B Cell-Activating Factor Receptor><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor 1 Gene><B-Cell Stimulatory Factor-1><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-1 Gene><BSF1><BSF1 Gene><Behavioral><Benign senescent forgetfulness><Binetrakin><Blood leukocyte><Body Tissues><Body fat><Brain><Brain Inflammation><Brain Nervous System><CD124 Antigens><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CDw124 Antigen><CNS Nervous System><Cardiovascular Pathology><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Central Nervous System><Central obesity><Centripetal obesity><Cerebrospinal Fluid><Cervical Lymph Node><Cervical lymph node group><Chronic><Clinical Research><Clinical Study><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cornu Ammonis><Cre driver><Cytokine Signal Transduction><Cytokine Signaling><Data><Dementia><Detection><Diabetes Mellitus><Differences between sexes><Differs between sexes><Dissection><Disturbance in cognition><Drug or chemical Tissue Distribution><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalitis><Encephalon><Epidemic><Exhibits><Experimental Models><Fats><Fatty Tissue><Fatty acid glycerol esters><Feedback><Female><Females in adulthood><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Glia><Glial Cells><Goals><Health><Height><High Fat Diet><Hippocampus><Homing><Hortega cell><Human><Hypertension><IL-13><IL-4><IL-4 Gene><IL-4 Receptors><IL13><IL4><IL4 Protein><IL4 Receptors><IL4 gene><Image><Immune><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impaired cognition><Inflammation><Innate Immunity><Integral Membrane Protein><Interleukin 4 Receptor><Interleukin-13><Interleukin-4><Interleukin-4 Gene><Interleukin-4 Precursor><Interleukin-4 Precursor Gene><Interleukin-4 Receptor Alpha><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Kolliker's reticulum><Leukocytes><Leukocytes Reticuloendothelial System><Light><Link><Lipectomy><Lymphatic cell><Lymphocyte><Lymphocyte Stimulatory Factor 1><Lymphocytic><MCGF-2><Machine Learning><Malus domestica><Maps><Marrow leukocyte><Masculine><Mast Cell Growth Factor-2><Measures><Meningeal><Meninges><Metabolic><Mice><Mice Mammals><Microglia><Modern Man><Morphology><Murine><Mus><Myeloid Cells><Native Immunity><Natural Immunity><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuroglia><Neuroglial Cells><Neuroimmune><Neurons><Neurophysiology / Electrophysiology><Non-Specific Immunity><Non-neuronal cell><Nonneuronal cell><Nonspecific Immunity><Obesity><Overnutrition><Pathogenesis><Pathology><Pattern><Pear><Peripheral><Photoradiation><Physiologic><Physiological><Physiopathology><Pilot Projects><Population><Predisposition><Prevalence><Primary Senile Degenerative Dementia><Publishing><Pyrus><Regulation><Reporter><Reporting><Risk><Risk Factors><Role><Route><Sex Differences><Sexual differences><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Susceptibility><Synapses><Synaptic><T-Cell Growth Factor 2><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Tamoxifen><Testing><Therapeutic><Tissue Distribution><Tissue Transplantation><Tissues><Toxin><Transmembrane Protein><Transmembrane Protein Gene><Transplantation Surgery><Truncal obesity><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Visceral><Weight><White Blood Cells><White Cell><Woman><Women in adulthood><Women's study><adipose><adiposity><age associated memory decline><age related cognitive deficit><age related cognitive impairment><age related memory dysfunction><age-induced cognitive decline><age-related decline in cognition><age-related decline in cognitive function><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><autocrine><autoimmune condition><autoimmune disorder><autoimmunity disease><biological sex><biological signal transduction><cell sorting><cerebral spinal fluid><co-morbid><co-morbidity><cognitive assessment><cognitive dysfunction><cognitive loss><cognitive testing><comorbidity><corpulence><cytokine><dementia risk><diabetes><diet-associated obesity><diet-induced obesity><diet-related obesity><dietary><dimorphism><electrophysiological><experiment><experimental research><experimental study><experiments><female study><flow cytophotometry><gitter cell><glial activation><glial cell activation><high blood pressure><hippocampal><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><imaging><induced Cre><inducible Cre><inducible expression><inducible gene expression><innovate><innovation><innovative><insight><lymph cell><lymphocyte trafficking><machine based learning><male><meninge><mesoglia><metabolic phenotype><metabotype><microglial cell><microgliocyte><nerve cement><neural inflammation><neuroinflammation><neuroinflammatory><neuronal><neuroprotection><neuroprotective><neutralizing antibody><novel><obesity risk><para-hydroxytamoxifen><pathophysiology><perivascular glial cell><pilot study><population aging><primary degenerative dementia><reconstruction><recruit><response><risk factor for dementia><risk for dementia><risk for obesity><risk of obesity><senile dementia of the Alzheimer type><sex based differences><sex dimorphism><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><sham surgery><social role><spinal fluid><study among females><study among women><study in females><study in women><study on females><study on women><study within women><subcutaneous><subdermal><synapse><tamoxifen metabolite B><thymus derived lymphocyte><trafficking><visceral obesity><weights><white adipose tissue><white blood cell><white blood corpuscle><yellow adipose tissue>