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Role of Macrophage Mechanobiology in Diabetic Gastroenteropathy
Summary Data Summary
Applicant Cipriani, Gianluca
E-Mail Address gianluca.cipriani@mayo.edu
Project Title Role of Macrophage Mechanobiology in Diabetic Gastroenteropathy
CBU ID 21AU4204
External SubContract ID 32307-90
Diabetic Complication Gastro-Intestinal (GI)
Funding Program Group Pilot & Feasibility [PF2021]
Abstract The long list of complications associated with diabetes mellitus includes
gastroenteropathies such as gastroparesis, a syndrome defined by delayed
emptying of gastric contents with no mechanical obstruction. Few treatments are
available for gastroparesis, which can be a disabling disorder due to not only
the symptoms of nausea, vomiting, early satiety, bloating and pain but also the
adverse impact of altered gastric emptying on glycemic control. It has become
clear that several cell types that regulate gastrointestinal motility are
important for gastroparesis' pathophysiology. Still, the most robust link is
between delayed gastric emptying and changes in macrophage polarization, which
associates with the loss of pacemaker cells (interstitial cells of Cajal, ICC)
in the gastric muscularis propria. Since gastroparesis is also associated with
stiffer tissues, and forces may activate macrophages, the impact of forces on
macrophage function may be especially relevant for macrophages in gastroparesis.
This proposal's overall hypothesis is that in gastroparesis, pro-inflammatory
Piezo1 macrophage release IL6, and TNFa in response to mechanical force, induce
loss of ICC and promote gastric dysfunction. We generated exciting preliminary
data for this application: 1) single-cell transcriptomics of CD45+ cells from
the gastric muscularis propria of mice identifies a population of gastric
macrophages expressing Piezo1, 2) Piezo1 macrophages are enriched in
pro-inflammatory genes, such as IL6 and TNFa in comparison to non Piezo1
macrophages that have a resident, non-inflammatory phenotype 3) We developed a
novel in-vitro primary culture of isolated macrophages that retain Piezo1
expression. We will test the hypothesis in 2 not overlapping AIMs.To test the
first AIM to determine how macrophages respond to mechanical force through
Piezo1 we will use a novel macrophage primary culture to determine the calcium
response and the cytokine release in the presence of a Piezo1 specific agonist.
To test the second AIM to determine the location of Piezo1 macrophages and the
effect of their depletion on gastric function in diabetic mice, we will generate
a diabetic Piezo1floxflox/Lyz2cre mouse model to study the effect of Piezo1
macrophages depletion on ICC and gastric emptying. This study is poised to
provide the mechanistic basis for understanding how mechanical cues lead to
macrophage activation in gastroparesis. Completion of the project will identify
new directions for testing novel options to treat both gastroparesis and other
complications of diabetes.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 43172
Supply Total Costs 12831
Equipment Total Costs 5890
Travel/Other Total Costs 1000
Direct Costs 62893
Indirect Costs Proposed 37107
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 7/1/2021
End Date 6/30/2022
IFO Name Grace, Janice S
IFO E-Mail Address researchadmin@mayo.edu
IACUC/IRB No. A00004326-20
IACUC/IRB Institution Mayo Clinic Rochester
Entity ID No.
Report Request Date 6/30/2022
T1D NO
TypeCount
Invoices 12
Progress Reports 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  21AU420432307-90Mayo Clinic Rochester9/30/2021$801.45$472.86$1,274.31-View PDF
  View  21AU420432307-90Mayo Clinic Rochester8/31/2022$1,607.33$913.49$2,520.82-View PDF
  View  21AU420432307-90Mayo Clinic Rochester7/31/2022$8,620.51$5,086.10$13,706.61-View PDF
  View  21AU420432307-90Mayo Clinic Rochester6/30/2022$9,826.88$5,797.87$15,624.75-View PDF
  View  21AU420432307-90Mayo Clinic Rochester5/31/2022$6,441.89$3,800.72$10,242.61-View PDF
  View  21AU420432307-90Mayo Clinic Rochester4/30/2022$11,233.47$6,627.78$17,861.25-View PDF
  View  21AU420432307-90Mayo Clinic Rochester3/31/2022$8,894.22$5,247.61$14,141.83-View PDF
  View  21AU420432307-90Mayo Clinic Rochester2/28/2022$3,536.36$2,086.45$5,622.81-View PDF
  View  21AU420432307-90Mayo Clinic Rochester12/31/2021$2,787.31$1,644.50$4,431.81-View PDF
  View  21AU420432307-90Mayo Clinic Rochester11/30/2021$4,398.73$2,595.24$6,993.97-View PDF
  View  21AU420432307-90Mayo Clinic Rochester10/31/2021$1,770.62$1,044.67$2,815.29-View PDF
  View  21AU420432307-90Mayo Clinic Rochester1/31/2022$2,996.19$1,767.75$4,763.94-View PDF
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