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Mitochondrial mechanisms of epigenetic dysregulation in diabetic gastroparesis
Summary Data Summary
Applicant Ordog, Tamas
E-Mail Address ordog.tamas@mayo.edu
Project Title Mitochondrial mechanisms of epigenetic dysregulation in diabetic gastroparesis
CBU ID 16GRU3727
External SubContract ID 30835-17
Diabetic Complication Gastro-Intestinal (GI)
Funding Program Group Pilot & Feasibility [PF2016]
Abstract Disordered control of smooth muscle function is common in gastrointestinal
diseases, which cost billions of dollars in health care spending each year.
Gastroparesis is one of the most significant manifestations of gastrointestinal
dysmotility, particularly in patients with diabetes mellitus. However,
therapeutic options are limited reflecting incomplete understanding of cellular
dynamics within the neuromuscular compartment. Previous research has identified
interstitial cells of Cajal (ICC) as the cell type most commonly affected in
gastroparesis. ICC serve as the physiological pacemaker for phasic contractile
activity and may partially mediate cholinergic excitatory and nitrergic
inhibitory neuromuscular neurotransmission. Diabetic ICC depletion may arise
from reduced Kit signaling, oxidative stress and macrophage action. A critical
gap in our knowledge is the lack of understanding of the fate of ICC lost from
these insults. Therefore, our main goal is to identify ICC fates, their
mechanisms and reversibility in diabetes. Using Cre-loxP technology-based
genetic lineage tracing, we have recently determined that in mice during the
first 3-5 months of postnatal life, nearly one-third of ICC dedifferentiate and
survive as cells lacking, or expressing very low levels of, the key ICC receptor
tyrosine kinase Kit. The same approach also detected abundant Kit(low/-) cells
genetically traceable from Kit(high) ICC in streptozotocin-diabetic mice,
indicating the existence of a cell population from which ICC can potentially
re-differentiate. Our central hypothesis is that this phenotypic ICC loss
arises, in part, from inhibition of 鈥渆rasers鈥 of key repressive epigenetic marks
due to disturbed mitochondrial metabolism. These changes then lead to silencing
of genes critical for ICC identity including Kit. In this pilot project we aim
to generate data supporting the role of succinate, a tricarboxylix acid cycle
metabolite that accumulates in diabetic tissues, in the epigenetic repression of
Kit and other ICC genes. We will employ RNA interference, in-vivo Cre-mediated
genome editing and epigenomic and phenotyping methods including the analysis of
genomic distribution of histone and DNA marks in relation to ICC gene
expression. To facilitate translation of our findings, we will also attempt to
restore ICC using epigenetic drugs already approved for use in humans. The
concept of manipulating interstitial cell populations via epigenetic
reprogramming of cells with persistently altered transcriptional programs will
change how we think about neuromuscular plasticity in health and disease.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 50990
Supply Total Costs 0
Equipment Total Costs 0
Travel/Other Total Costs 11903
Direct Costs 62893
Indirect Costs Proposed 37107
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 10/1/2016
End Date 9/30/2017
IFO Name Moertel, David
IFO E-Mail Address researchadmin@mayo.edu
IACUC/IRB No. IACUC:A48315; IRB:07-003371
IACUC/IRB Institution Mayo Clinic Rochester
Entity ID No. 1416011702A1
Report Request Date 10/30/2017
T1D NO
TypeCount
Invoices 7
Progress Reports 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  16GRU372730835-17Mayo Clinic Rochester7/31/2017$6,324.22$3,731.29$10,055.51$15,246.57View PDF
  View  16GRU372730835-17Mayo Clinic Rochester6/30/2017$5,776.58$3,408.19$9,184.77$15,246.57View PDF
  View  16GRU372730835-17Mayo Clinic Rochester5/31/2017$6,743.66$3,978.76$10,722.42$15,246.57View PDF
  View  16GRU372730835-17Mayo Clinic Rochester4/30/2017$5,098.44$3,008.09$8,106.53$15,246.57View PDF
  View  16GRU372730835-17Mayo Clinic Rochester3/31/2017$20,963.74$12,368.58$33,332.32$15,246.57View PDF
  View  16GRU372730835-17Mayo Clinic Rochester2/28/2017$3,025.21$1,784.87$4,810.08$15,246.57View PDF
  View  16GRU372730835-17Mayo Clinic Rochester1/31/2017$5,372.20$3,169.60$8,541.80$15,246.57View PDF


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