Document text
Principal Investigator: Julia V Busik
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $379,250
Funding agency: National Eye Institute
Abstract
Bone marrow (BM)-derived vascular reparative cells, called myeloid angiogenic cells or MACs, are critical in
vascular repair due to their ability to release growth factors and immunomodulatory proteins that promote
endothelial survival and proliferation. MAC dysfunction in diabetes may lead to the imbalance between
physiological repair and pathological inflammation. Cholesterol levels are pathologically increased in MACs
from diabetic humans and mice leading to their dysfunction. Liver X receptor (LXR) activation restores
membrane fluidity in the diabetic MACs and facilitates cell migration and vascular repair preventing
vasodegenerative damage in the retinas of db/db mice (type 2 diabetes model). Recently, we made the novel
observation that MACs are preferentially mobilized to the injured retina from the calvaria BM and not the long
bones, while proinflammatory myeloid cells (myelopoiesis) are preferentially mobilized from the long bones.
Calvaria BM does not increase in fat content with increasing age, whereas the long bones do (promoting
myelopoiesis), supporting that the calvarium may be resilient to the adverse metabolic consequences of
chronic diabetes. While we showed denervation in the long bones in STZ-induced T1D, T2D db/db mice and
T2D rats (promoting myeloidosis), Ferraro et. al. identified neurogenesis in the calvarium of diabetic mice
suggesting a differential response to diabetes in these two distinct BM compartments. Importantly, unlike the
long bones, the calvarium is directly connected to the cerebral spinal fluid (CSF), a source of neurotropic and
growth factors including endogenous LXR ligands. Hypothesis: In contrast to the long bones, the calvaria
BM compartment is resistant to the adverse impact of diabetes because the CSF provides it with
neurotrophic and growth factors sustaining hematopoiesis and adequate levels of MACs needed for
vascular repair of the retina. In contrast, long bones succumb to denervation and myelopoiesis.
Overtime, however, the calvarium loses this protective response shifting the balance towards systemic
inflammation and development of DR. To evaluate this hypothesis, we propose the following aims.
Aim 1: To interrogate the calvarium microenvironment (stromal cells, resident BM macrophages, and
hematopoietic cells) by examining innervation by the sympathetic nervous system and changes in
hematopoiesis over the time course of diabetes.
Aim 2: To determine the time course of diabetes-induced changes in the release of BM compartment-specific
myeloid cells and MACs that are recruited to the retina.
Aim 3: To restore calvaria BM compartment in late-stage diabetes using targeted delivery of LXR agonists.
Terms: <Adrenergic Agents><Adrenergic Drugs><Adrenergics><Adult-Onset Diabetes Mellitus><Age><Agonist><Aujeszky's Disease Virus><Aujeszkys Disease Virus><Autonomic nervous system><Back><Bilayer Fluidity><Blood Vessels><Blood capillaries><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Reticuloendothelial System><Brain><Brain Nervous System><Brittle Diabetes Mellitus><Calvaria><Cell Body><Cell Isolation><Cell Locomotion><Cell Migration><Cell Movement><Cell Segregation><Cell Separation><Cell Separation Technology><Cell membrane><Cells><Cellular Migration><Cellular Motility><Cerebrospinal Fluid><Cholesterol><Chronic><Common Rat Strains><Complications of Diabetes Mellitus><Cytoplasmic Membrane><Denervation><Development><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Complications><Diabetic Retinopathy><Diabetic mouse><Disease><Disease Progression><Disorder><Dorsum><Drugs><Dura><Dura Mater><Dysfunction><Encephalon><Endothelium><Equilibrium><Fats><Fatty acid glycerol esters><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Generations><Growth Agents><Growth Factor><Growth Substances><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Herpesvirus 1 (alpha), Suid><Herpesvirus Suis><Human><Hydrogels><IDDM><Immune><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunomodulation><Inflammation><Inflammatory><Injury><Insulin-Dependent Diabetes Mellitus><Intraventricular><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Ligands><Liver X Receptor><Macrophage><Marrow monocyte><Maturity-Onset Diabetes Mellitus><Medication><Membrane Fluidity><Metabolic><Metabolic stress><Mice><Mice Mammals><Microscopic><Modeling><Modern Man><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Myelopoiesis><Mφ><NIDDM><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Pathogenesis><Pathologic><Pharmaceutical Preparations><Phase><Phenotype><Physiologic><Physiological><Physiopathology><Plasma Membrane><Population><Proliferating><Proteins><Proteins Growth Factors><Pseudorabies virus><Rat><Rats Mammals><Rattus><Receptor Activation><Red Marrow><Reporter><Resistance><Retina><Rodent Model><Role><STZ><Skull><Slow-Onset Diabetes Mellitus><Source><Stable Diabetes Mellitus><Streptozocin><Streptozotocin><Stromal Cells><Sudden-Onset Diabetes Mellitus><Suid Herpesvirus 1><Swine Herpesvirus 1><Sympathetic Nervous System><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Testing><Therapeutic><Time><Tissues><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Tyrosine 3-Monooxygenase><Tyrosine Hydroxylase><Vascular blood supply><Yellow Marrow><Zanosar><adult onset diabetes><ages><balance><balance function><blood cell formation><blood supply><bone><calvarial><capillary><cell motility><cell sorting><cerebral spinal fluid><cranium><db/db mouse><developmental><diabetes><diabetes mouse model><diabetic><drug/agent><flow cytophotometry><hemopoietic><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><injured><injuries><innervation><insulin dependent diabetes><insulin dependent type 1><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><long bone><mad itch virus><maturity onset diabetes><monocyte><nerve supply><neurogenesis><neuronal><neurotrophic factor><neurotrophin><neurotropic><neutrophin><novel><pathophysiology><pharmacologic><plasmalemma><post-natal development><postnatal development><prevent><preventing><progenitor><protective factors><recruit><repair><repair function><repaired><reparative function><resilience><resilient><resistant><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><site targeted delivery><social role><spinal fluid><stem><systemic inflammation><systemic inflammatory response><targeted delivery><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes><vascular><vascular supply>