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Targeting PKM2 in chronic hypoperfusion for the treatment of cognitive impairment in type 2 diabetes
Summary Data Summary
Applicant Simao, Fabricio
E-Mail Address fabricio.simao@joslin.harvard.edu
Project Title Targeting PKM2 in chronic hypoperfusion for the treatment of cognitive
impairment in type 2 diabetes
CBU ID 21AU4185
External SubContract ID 32307-89
Diabetic Complication Neuropathy & Neurocognition
Funding Program Group Pilot & Feasibility [PF2021]
Abstract Type 2 diabetes (T2D) is associated with morphologic changes in brain structure,
including brain atrophy, white matter lesions, hypoperfusion and stroke leading
to cognitive changes mainly affecting learning and memory. Although the causes
for vascular cognitive impairment and dementia (VCID) are not clear, increasing
evidence suggests cerebral hypoperfusion is the dominant pathogenic process.
There is an urgent need to understand the mechanisms involved and the
development of new therapeutic strategies to reverse the cognitive decline.
Recent studies have indicated that pyruvate kinase M2 (PKM2) mediated signaling
plays a crucial role, not only in regulating glycolysis, but also in many
cellular functions including proliferation, inflammation and mitochondrial
stress. Furthermore, oxidative metabolism in different cells contributes
significantly to the pathogenesis of T2D. The role of metabolism in astrocyte
function is not well studied, and the role of astrocytes in T2D pathogenesis of
VCID is completely unknown. We hypothesize that disturbance of PKM2 signaling in
astrocyte cells underlies the pathogenesis of VCID in T2D. To test this
hypothesis, we have generated an animal model of cognitive impairment-induced by
chronic hypoperfusion in T2D. Our preliminary data show an increase in PKM2
protein levels and a decrease in enzymatic activity in hippocampus of VCID mice
with T2D, indicating a novel molecular mechanism mediated by glucose metabolism
in cognitive decline. Moreover, VCID mice with T2D induce PKM2 translocation to
the nucleus and an increased nuclear HIF-1alpha expression in the hippocampus.
These perturbations were followed by high levels of several inflammatory markers
in the hippocampus. In this proposal, we will use a conditional PKM2 knockout in
astrocytes and a pharmacological PKM2 activator to test our hypothesis by
addressing the following questions: (1) whether PKM2 in astrocytes contributes
to the overall metabolic disorders that underlies the pathogenesis of cognitive
decline, blood brain barrier leakage and inflammation evident in VCID mice with
T2D; and (2) whether a PKM2 activator may represent a therapeutic strategy
against VCID mice with T2D. Collectively, these studies will determine how PKM2
in astrocytes contributes to cognitive decline in T2D, and how PKM2 affects
brain inflammation and permeability, and glucose metabolism in VCID mice with
T2D. Ultimately, we will test if a PKM2 activator is a novel therapeutic
strategy for VCID patients with T2D.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel Fabricio Simao, PI
Salary Total Costs 55817
Supply Total Costs 17710
Equipment Total Costs 0
Travel/Other Total Costs 17382
Direct Costs 90909
Indirect Costs Proposed 9091
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 7/1/2021
End Date 6/30/2022
IFO Name Fabrizio, Diane
IFO E-Mail Address diane.fabrizio@joslin.harvard.edu
IACUC/IRB No. 09-09
IACUC/IRB Institution Joslin Diabetes Center
Entity ID No. 04-2203836
Report Request Date 6/30/2022
T1D NO
TypeCount
Invoices 10
Progress Reports 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  21AU418532307-89Joslin Diabetes Center8/15/2022$11,835.76$1,183.58$13,019.34$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center6/15/2022$4,891.43$489.14$5,380.57$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center5/16/2022$6,101.23$610.12$6,711.35$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center4/19/2022$16,726.74$1,672.67$18,399.41$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center3/16/2022$13,220.48$1,322.05$14,542.53$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center2/17/2022$4,424.85$442.49$4,867.34$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center12/13/2021$9,308.72$930.87$10,239.59$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center11/16/2021$4,607.34$460.73$5,068.07$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center10/19/2021$14,091.51$1,409.15$15,500.66$1,001.68View PDF
  View  21AU418532307-89Joslin Diabetes Center1/13/2022$4,790.42$479.04$5,269.46$1,001.68View PDF


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