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
2015-08-15 | GSE70752 | GEO
Project description:Macrophage dysfunction and polarization plays key role in chronic inflammation associated with diabetes and its complications. However, the effect of diabetes on macrophage transcriptome including long non-coding RNAs is not known. Here, we analyzed global changes in transcriptome of bone marrow macrophages isolated from type 2 diabetic db/db mice and control littermates db/+ mice using high throughput RNA-seq technique. Data analysis showed that expression of genes relevant to fibrosis, cell adhesion and inflammation were altered in diabetic db/db mice relative to control db/+ mice. Furthermore, expression of several known and novel long non coding RNAs and nearby genes was altered in db/db mice. Gene ontology and IPA showed activation of signaling netwroks relevant to fibrosis, cell adhesion and inflammatory pathways . This study for the first time demonstrated that diabetes profoundly affects macrophage transcriptome including expression of long non coding RNAs and altered the levels of genes relevant to diabetes complications. Bone marrow macrophages were isolated from 12 weeks old type 2 diabetic male db/db mice and control littermates db/+ mice. These were differentiated in culture for 7-8 days in the presence of 10 ng/ml of MCSF-1 (BMMC) or 20 ng/ml of GM-CSF (BMGM). Then RNA was extracted and used for RNA-seq.
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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
of information on the impact of intensive therapy on glycemia and the its long-term complications for persons with Type 1 diabetes.
</p>
<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
they apply to late-occurring complications, such as cardiovascular disease and more advanced stages of retinal and renal disease (3).
The EDIC study has been remarkably fruitful in discovering the long term "imprinting" effects (metabolic memory) of the previous intensive
therapy, and in delineating the interactions among risk factors with regard to microvascular complications (4-6). In addition, EDIC
established, for the first time, the role of intensive therapy and chronic glycemia on atherosclerosis (7-9).
</p>
<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>
| phs000086.v2.p1 | EGA
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Project description:Monocyte activation by high glucose and free fatty acids promotes inflammation implicated in vascular complications associated with Type 2 diabetes (T2D). Emerging evidence shows that long non coding RNA (lncRNA)s regulate inflammation, but their role in T2D induced monocyte dysfunction is unclear. To examine this, we profiled the transcriptome of CD14+ monocytes from volunteers with T2D and without diabetes (n=5 each) using strand-specific RNA-seq on Illumina HiSeq 2500. Our study identified several differentially regulated lncRNAs along with coding genes involved in monocyte functions related to inflammation and monocytosis.
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Project description:Background—Diabetes is a prevalent public health problem that affects about one third of the U.S. population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes complications is incompletely understood. We thus investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. Methods and Results—In three types of mouse diabetes, we observed enhanced proliferation of hematopoietic stem and progenitor cells (HSPC) leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (EGFR) signaling in mice with diet-induced diabetes. To explore whether endothelial EGFR plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of EGFR (Cdh5Cre EGFRfl/fl). Unexpectedly, we found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre EGFRfl/fl mice compared to wild type mice with diabetes. Disrupted EGFR signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre EGFRfl/fl mice, significantly delaying wound closure. Atherosclerosis accelerated in Cdh5Cre EGFRfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta. Conclusions—In diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis and promote cardiovascular complications via leukocyte overproduction. Specifically, diabetes reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We also describe a previously unknown counter-regulatory pathway, in which protective endothelial EGFR signaling curbs HSPC proliferation and myeloid cell production via angiopoietin-1.
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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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Project description:Macrophage dysfunction and polarization plays key role in chronic inflammation associated with diabetes and its complications. However, the effect of diabetes on macrophage transcriptome including long non-coding RNAs is not known. Here, we analyzed global changes in transcriptome of bone marrow macrophages isolated from type 2 diabetic db/db mice and control littermates db/+ mice using high throughput RNA-seq technique. Data analysis showed that expression of genes relevant to fibrosis, cell adhesion and inflammation were altered in diabetic db/db mice relative to control db/+ mice. Furthermore, expression of several known and novel long non coding RNAs and nearby genes was altered in db/db mice. Gene ontology and IPA showed activation of signaling netwroks relevant to fibrosis, cell adhesion and inflammatory pathways . This study for the first time demonstrated that diabetes profoundly affects macrophage transcriptome including expression of long non coding RNAs and altered the levels of genes relevant to diabetes complications.
2014-09-15 | GSE54154 | GEO
Project description:BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, non-invasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without (testing set: AUC = 0.85, 95%CI, 0.73-0.96), outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84, 95%CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, non-invasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.
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