Document text
Principal Investigator: Joana Almaca
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $368,400
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
The coronavirus disease 2019 (COVID-19) is a global healthcare crisis that in the USA kills about 1 person every
minute. It is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). While respiratory
failure is still the most common cause of mortality in COVID-19 patients, serious manifestations are seen across
multiple organs, including the pancreas. There is an intricate relationship between COVID-19 and pancreatic
diseases such as pancreatitis and diabetes. Understanding the pathophysiological mechanisms that lead to
pancreatic dysfunction and glucose intolerance in infected patients is of utmost importance. The pathogenesis
of diabetes is intimately associated with the dysfunction of the pancreatic islet. There are numerous studies
indicating that SARS-CoV-2 directly attacks the vascular system. However, the possibility that islet microvascular
dysfunction triggers loss of glucose homeostasis in COVID-19 patients has not been explored. This project
focuses on the vascular pericyte because our published and preliminary data show that (a) pericytes in human
islets are very responsive to angiotensin II and express the key host cellular receptor of SARS-CoV-2, ACE2;
(b) pericytes can be infected with SARS-CoV-2 pseudo-entry viruses; and (c) incubation with a SARS-CoV-2
Spike recombinant protein increases pericyte basal Ca2+ levels. We therefore hypothesize that SARS-CoV-2
infects pancreas pericytes, interfering with their contractile properties and impairing their function. Pericyte
dysfunction will decrease local blood flow, leading to tissue hypoxia and inflammation and compromising
endocrine cell activity. We will test this hypothesis using living pancreas slices from humans and hamsters which
are a suitable animal model for COVID-19 research given the high homology of their ACE2 protein sequences.
This hypothesis will be tested in two Aims: 1) determine if pericytes are cellular targets of SARS-CoV-2 in the
pancreas, and (2) examine the effects of SARS-CoV-2 on islet pericyte function and microvascular responses
ex vivo and in vivo. In Aim 1, we will search for SARS-CoV-2 viral particles, characterize microvascular lesions
and the pericyte phenotype in the pancreas of COVID-19 patients. We will infect living pancreas slices with
SARS-CoV-2 pseudo-entry and live viruses and determine if pericytes are permissive for infection. In Aim 2, we
will assess the functional consequences of manipulating ACE2 expression and activity through interactions with
SARS-CoV-2 spike protein on pericyte Ca2+ responses and vasomotion ex vivo in living pancreas slices, and in
vivo by intraductal injections of pseudo-entry viruses in the hamster pancreas. We will follow longitudinally the
effects on glucose metabolism, as well as changes in local hypoxia, inflammation, endocrine cell mass and
function. This research has the potential to identify a mechanism of dysfunction in the endocrine pancreas. If the
hypothesis is correct, pericytes are cellular targets of this coronavirus. Their functional impairment could explain
why COVID-19 is linked to a loss of glucose homeostasis and other pancreatic disorders. We anticipate our
study of COVID-19–related diabetes to uncover novel mechanisms of the natural history of this disease.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Adventitial Cell><Affect><Airway failure><Amino Acid Sequence><Ang I (1-7)><AngII><Angiotensin II><Animal Model><Animal Models and Related Studies><Autopsy><B9 endocrine pancreas><Blood Glucose><Blood Sugar><Blood Vessels><Blood flow><Body Tissues><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cell Body><Cells><CoV emergence><CoV-2><CoV2><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Cricetinae><Data><Diabetes Mellitus><Dysfunction><Endocrine><Endocrine Pancreas><Endocytosis><Functional disorder><Functional impairment><Glucose Intolerance><Hamsters><Hamsters Mammals><Health><Healthcare><Hormone secretion><Human><Hypoxia><Hypoxic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impairment><Incubated><Infection><Infiltration><Inflammation><Injections><Islands of Langerhans><Islets of Langerhans><Lesion><Link><Lung><Lung Respiratory System><Microvascular Dysfunction><Modeling><Modern Man><Nesidioblasts><Organ><Oxygen Deficiency><Pancreas><Pancreatic><Pancreatic Diseases><Pancreatic Disorder><Pancreatic Islets><Pancreatitis><Pars endocrina pancreatis><Patients><Pattern><Pericapillary Cell><Pericytes><Perivascular Cell><Persons><Phenotype><Physiopathology><Predisposition><Primary Protein Structure><Property><Proteins><Publishing><Receptor Protein><Recombinant Proteins><Recombinants><Research><Research Specimen><Respiratory Failure><Rouget Cells><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Slice><Specimen><Surface><Susceptibility><Testing><Time><Tissues><Tropism><Vascular System><Vascularization><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Viral><Viral Diseases><Viral Receptor><Virus><Virus Diseases><Virus Receptors><Wuhan coronavirus><angiotensin I (1-7)><angiotensin converting enzyme 2><angiotensin converting enzyme II><angiotensin-(1-7)><blood glucose regulation><cellular targeting><corona virus><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><diabetes><diabetes pathogenesis><disease natural history><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><global health><glucose control><glucose homeostasis><glucose metabolism><glucose regulation><hCoV19><health care><histopathologic examination><histopathological examination><hormonal secretion><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><islet><islet progenitor><microvascular complications><microvascular disease><model of animal><mortality><nCoV><nCoV2><necropsy><new CoV><new corona virus><new coronavirus><non-diabetic><nondiabetic><novel><novel CoV><novel corona virus><novel coronavirus><pancreas disorder><particle><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><permissiveness><postmortem><protein sequence><pulmonary><receptor><response><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><small molecular inhibitor><small molecule inhibitor><small vessel disease><spatiotemporal><spike proteins on SARS-CoV-2><vascular><vascular constriction><vasoconstriction><vasomotion><viral infection><virus infection><virus-induced disease>