Type 1 Diabetes DNA Damage Checkpoint Pathway Quantitation
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Velos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: Rohit Kulkarni
PROVIDER: MSV000079185 | MassIVE | Wed Jul 08 14:01:00 BST 2015
SECONDARY ACCESSION(S): PXD002504
REPOSITORIES: MassIVE
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Project description:Preserved DNA Damage Checkpoint Pathway Protects From Complications in Long-standing Type 1 Diabetes
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Project description:Gene expression analyses of fibroblasts obtained from healthy controls, Medalist -C patients and Medalist +C patients. Type 1diabetes (T1D) is associated with late complications, mechanisms underscoring which are poorly understood. We report the derivation of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50years) with severe (designated Medalist +C) or absent to mild complications (designated Medalist -C). Disease modeling of iPSCs revealed impairment in growth, reprogramming and differentiation in Medalist +C. Further investigations using genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist –C. In silico analyses revealed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs showed enhanced susceptibility to genotoxic stress that worsened upon miR200 over-expression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage response. In summary, we report miR200 regulated DNA damage checkpoint pathway as a potential target for therapeutic intervention for treating complications of diabetes. Clinical Characteristics of 50 year Medalist Type 1 Diabetes (T1D) patients Medalist –C: 0/6 with CVD, 5/6 have DN Class 0-IIA, and 6/6 have no to mild NPDR. Medalist +C: 6/6 with CVD, 5/6 have DN Class IIB or IV, and 4/6 have PDR. CVD: cardiovascular disease; DN class: diabetic nephropathy class, PDR: proliferative diabetic retinopathy; NPDR: non proliferative diabetic retinopathy
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Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
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Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
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Project description:<p>The Diabetes Control and Complications Trial (DCCT, 1982-93) and the Epidemiology of Diabetes Interventions and Complications
follow-up study (EDIC, 1994-2016) have been ongoing for more than twenty years. After a mean follow-up of approximately 16 years,
the DCCT-EDIC cohort of 1,441 Type 1 diabetics had remained remarkably complete with more than 90% of the original cohort being
actively followed. Taken together, the DCCT clinical trial and subsequent EDIC longitudinal follow-up provide a uniquely rich source
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<p>The DCCT was a multicenter, randomized clinical trial (1, 2) designed to compare intensive with conventional diabetes therapy with regard
to their effects on the development and progression of the early complications of Type 1 diabetes. The DCCT trial found that "intensive
therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy" in patients with Type
1 diabetes (1). The goal of the EDIC follow-up was to examine the longer term effects of the original DCCT interventions, especially as
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The EDIC study has been remarkably fruitful in discovering the long term "imprinting" effects (metabolic memory) of the previous intensive
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<p><b>Note:</b> This study description has been prepared using materials authored by the DCCT-EDIC Data Coordinating Center.</p>
<p><a href="GetPdf.cgi?id=phd000390" target="_blank">DETAILED DESCRIPTION OF STUDY</a></p>
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Project description:In this study, we examined the impact of modulating the TGF-β/PAI-1 axis in CD34+ cells function from diabetic patients and controls. Using gene array studies, we found that diabetics, protected from microvascular complications despite suboptimal glycemic control, had reduced level of TGF- β1 and PAI-1 transcripts in their CD34+ cells compared to age, sex, duration and degree of glycemic control -matched diabetics with microvascular complications. Treatment with neutralizing antibody to TGF- β1 in murine hematopoietic stem cells (HSC) enhanced in vivo repopulation potential of these cells in bone marrow transplantation; reduced the time required for cell division of single cells, increased survival of the progenitor cells and reduced TGF-β1 expression. TGF- β1 phosphorodiamidate morpholino oligomers (PMO) treatment reduced PAI-1 mRNA expression in diabetic (p<0.01) and non-diabetic (p=0.05) CD34+ cells. Inhibition of PAI-1 promoted CD34+ cell proliferation and migration in vitro.Targetting TGFβ-1/PAI-1 system offers a promising therapeutic strategy for restoring vascular reparative function in diabetic CD34+ cells and hematopoietic stem cells, enhancing key functions needed for cell therapy. Peripheral blood from either age matched controls (n=5), diabetics with long standing poorly controlled diabetes and no microvascular complications (n=4), and diabetics with long-standing poorly controlled diabetes with severe microvascular complications (n=5) was obtained and CD34+ cells were isolated. RNA was extracted followed by AffyNugen amplification, and the cDNA was probed to Human RSTA Affymetrix 2.0 chip
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Project description:Microvascular complications are the major outcome of type 2 diabetes mellitus progression and the underlying mechanism remains to be determined. To explore the contribution of circulating monocytes to the microvascular lesions, high-throughput RNA sequencing was conducted and we found high-level expression of cathepsin D (CTSD) in the monocytes of type 2 diabetes mellitus patients. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied with cognitive deficit. Mechanistically, we found the monocytes release non-enzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low density lipoprotein receptor-related protein 1 (LRP1). Importantly, genetic ablation of CTSD in the monocytes exhibited protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. Our findings thus uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is thus a potential target for the intervention of microvascular complications in diabetes.
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