ACE2 Modulates the Bone Marrow- Gut Axis in Diabetic Retinopathy

NIH Pandemic-Era Grants

Pandemic Era Grants

2019

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Principal Investigator: Michael Edwin Boulton
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2019
Award: $403,279
Funding agency: National Eye Institute

This proposal examines the hypothesis that diabetes results in a pathological change in the
communication between the bone marrow (BM) and gut leading to dysfunction in both
compartments. Angiotensin converting enzyme 2 (ACE2) converts angiotensin II (ANG II) to
angiotensin 1-7(Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the
molecular and cellular effects of ANG II. In human subjects with diabetes, sustained activation
of the ACE2/Ang 1-7/Mas axis in a key BM population (CD34+ cells) was associated with
protection from development of diabetic retinopathy. Ace2/Ace1 mRNA ratio was reduced in
small intestine epithelial cells (IEC) and in BM cells of diabetic mice and these changes are
associated with both gut and BM pathology. Microbiota studies comparing Akita mice and Ace2-
/- Akita mice demonstrate that the loss of ACE2 results in significant phylogenetic differences
and these changes are associated with increased infiltration of proinflammatory BM cells into
the gut.
 These novel findings have led us to propose the following hypothesis: Dysregulated RAS
resulting in reduced ACE2 in BM and gut drives the disturbed BM-gut axis in diabetes.
Increasing ACE2 expression in BM or IEC, either by genetic or pharmacological
manipulations, will restore reciprocal communication between BM and gut preventing
development of diabetic retinopathy.
 Aim 1: In Akita mice, to determine whether increasing ACE2 expression in hematopoietic
cells will facilitate maintenance of endothelial and epithelial barrier functions in retina and gut.
Hematopoietic-specific Ace2 transgenic mice (Vav1-CreAce2KI) will be crossed with Akita mice
to generate Vav1-CreAce2KI.Akita mice (Model 1). Vav1-CreAce2KI will provide donor BM for
BM transplantation into Akita mice (Model 2).
 Aim 2: To determine whether sustained ACE2 expression in hematopoietic cells will prevent
diabetes-induced dysbiosis and development of DR.
 Aim 3. To determine whether correction of dysbiosis by exogenous administration of
genetically modified probiotics expressing ACE2 or overexpression of ACE2 in intestinal
epithelial cells of the gut will protect from development of DR.

Terms: <ACE Inhibitors><Acute><Amphoterin Gene><Ang-2><Ang2><AngII><Angiopoietin-2><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin II><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensins><Anterior><B220><Bacteria><Blood Serum><Blood monocyte><Blood-Retinal Barrier><Body Tissues><Bone Development><Bone Marrow><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><CD143 Antigens><CD34><CD34 gene><CD45><Carboxycathepsin><Causality><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Chromosomal Protein, Nonhistone, HMG1 Gene><Communication><Development><Diabetes Mellitus><Diabetic Retinopathy><Diabetic mouse><Dipeptidyl Peptidase A><Dysfunction><Endothelium><Engineered Probiotics><Enzyme Gene><Enzymes><Epithelial><Epithelial Cells><Equilibrium><Etiology><Functional disorder><GI microbiota><GP180><Gastrointestinal microbiota><Genetic><Gut Epithelium><Gut Inflammation><HMG-1 Gene><HMG1 Gene><HMG3 Gene><HMGB1><HMGB1 gene><HPCA1><Hematopoietic><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1 Gene><Human><Hyperactive behavior><Hyperactivity><Hyperkinesia><Hyperkinesis><Hyperkinetic Movements><Hypertension><Immune><Immunes><Individual><Infiltration><Inflammation><Inflammatory disease of the intestine><Inflammatory disorder of the intestine><Intestinal><Intestinal Inflammation><Intestines><Kininase A><Kininase II><Kininase II Antagonists><Kininase II Inhibitors><LY5><Lactobacillus><Lipopolysaccharides><Maintenance><Marrow Transplantation><Marrow monocyte><Measures><Mediating><Messenger RNA><Mice><Mice Mammals><Microvascular Dysfunction><Modeling><Modern Man><Modified Probiotics><Molecular><Motor Hyperactivity><Murine><Mus><Myeloid Cells><Nonhistone Chromosomal Protein HGM1 Gene><Oxidative Stress><PTPRC><PTPRC gene><Pathogenesis><Pathologic><Pathology><Peptidyl-Dipeptidase A><Pharmacology><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Phylogenetic Analysis><Phylogenetics><Physiopathology><Population><Probiotic Engineering><Probiotics><Receptor Protein><Recombinants><Renin-Angiotensin System><Resolution><Retina><Retinal Diseases><Retinal Disorder><SBP-1 Gene><Serum><Small Intestines><Subcellular Process><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Supplementation><T200><Time><Tissues><Transgenic Mice><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><arm><bacterial community><balance><balance function><bowel><causation><cohort><developmental><diabetes><diabetes mouse model><diabetic><disease causation><dysbacteriosis><dysbiosis><dysbiotic><enteric microbial community><enteric microbiota><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><gastrointestinal epithelium><gastrointestinal microbial flora><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><hemopoietic><high blood pressure><human subject><hyperpiesia><hyperpiesis><hypertensive disease><improved><intestinal flora><intestinal microbes><intestinal microbiota><intestinal microflora><intestinal tract microflora><mRNA><metatranscriptomics><microbial antigen><microbial consortia><microbial flora><microbial imbalance><microbiota><microflora><microorganism antigen><microvascular complications><microvascular disease><monocyte><mouse model><multispecies consortia><murine model><novel><overexpress><overexpression><pathophysiology><phase 2 trial><phase II protocol><prevent><preventing><receptor><recruit><retina disease><retina disorder><retinopathy><small bowel><small vessel disease>