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Exosomal proteomic profiling revealed children type 1 diabete pathogenesis and potential therapeutic targets

ABSTRACT: Abstract Introduction: Type 1 diabetes (T1D) is a serious autoimmune disease with high morbidity and mortality. Early diagnosis and treatment remain unsatisfactory. Circulating exosomes containing T1D biomarkers have gained interest, but progress is limited. Objectives: This study investigates molecular dynamics of plasma exosomes in pediatric T1D patients and reveals potential mechanisms associated with T1D development. Methods: Liquid chromatography-tandem mass spectrometry with TMT6 labeling quantified exosomal protein expression profiles in 12 healthy and 24 pediatric T1D patients, stratified by age (≤6 years and >6 years) and glycated hemoglobin (HbA1c) levels (>7% or ≤7%). Integrative bioinformatics analyses were conducted, and Western Blot (WB) validated findings. Results: We identified 1035 proteins, revealing 548 and 589 differentially expressed proteins (fold change >1.3) in T1D patients aged ≤6 and >6 years, respectively. When HbA1c was below 7% (received insulin therapy for at least three months), most of the altered protein levels in both age groups resembled healthy controls. Bioinformatics analysis indicated exosome components related to immune functions, hemostasis, cellular stress response, and extracellular matrix organization. WB confirmed alterations in RAB40A, COL6A5, SEMA6D, and TTR proteins. Conclusion: Our study characterizes plasma exosome protein dynamics in pediatric T1D patients across age stages, providing valuable insights into molecular mechanisms and identifying potential therapeutic targets for T1D management.

ORGANISM(S): Homo Sapiens

SUBMITTER: Qin Zhang

PROVIDER: PXD043146 | iProX | Tue Jun 20 00:00:00 BST 2023

REPOSITORIES: iProX

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Pathological mechanisms of type 1 diabetes in children: investigation of the exosomal protein expression profile.

Bai Baoling B Gao Kang K Zhang Kexin K Liu Lingyun L Chen Xiaobo X Zhang Qin Q

Frontiers in endocrinology 20231011

<h4>Introduction</h4>Type 1 diabetes (T1D) is a serious autoimmune disease with high morbidity and mortality. Early diagnosis and treatment remain unsatisfactory. While the potential for development of T1D biomarkers in circulating exosomes has attracted interest, progress has been limited. This study endeavors to explore the molecular dynamics of plasma exosome proteins in pediatric T1D patients and potential mechanisms correlated with T1D progression.<h4>Methods</h4>Liquid chromatography-tande ...[more]

PMID: 37886648

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Project description:Introduction: microRNAs are promising candidate breast cancer biomarkers due to their cancer-specific expression profiles. However, efforts to develop circulating breast cancer biomarkers are challenged by the heterogeneity of microRNAs in the blood. To overcome this challenge, we aimed to develop a molecular profile of microRNAs specifically secreted from breast cancer cells. Our first step towards this direction relates to capturing and analyzing the contents of exosomes, which are small secretory vesicles that selectively encapsulate microRNAs indicative of their cell of origin. To our knowledge, circulating exosome microRNAs have not been well evaluated as biomarkers for breast cancer diagnosis or monitoring. Methods: Exosomes were collected from the conditioned media of human breast cancer cell lines, mouse plasma of patient-derived orthotopic xenograft models (PDX), and human plasma samples. Exosomes were verified by electron microscopy, nanoparticle tracking analysis, and western blot. Cellular and exosome microRNAs from breast cancer cell lines were profiled by next-generation small RNA sequencing. Plasma exosome microRNA expression was analyzed by qRT-PCR analysis. Results: Small RNA sequencing and qRT-PCR analysis showed that several microRNAs are selectively encapsulated or highly enriched in breast cancer exosomes. Importantly, the selectively enriched exosome microRNA, human miR-1246, was detected at significantly higher levels in exosomes isolated from PDX mouse plasma, indicating that tumor exosome microRNAs are released into the circulation and can serve as plasma biomarkers for breast cancer. This observation was extended to human plasma samples where miR-1246 and miR-21 were detected at significantly higher levels in the plasma exosomes of 16 breast cancer patients as compared to the plasma exosomes of healthy control subjects. Receiver Operating Characteristic (ROC) curve analysis indicated that the combination of plasma exosome miR-1246 and miR-21 levels is a better indicator of breast cancer than their individual levels. Conclusions: Our results demonstrate that certain microRNA species, such as miR-21 and miR-1246, are selectively enriched in human breast cancer exosomes and significantly elevated in the plasma of breast cancer patients. These findings indicate a potential new strategy to selectively analyze plasma breast cancer microRNAs indicative of the presence of breast cancer.

Project description:Goal: To compare the gene expression profiles from pediatric patients with each other, with those reported in adults and in those related to exosomes. Background: Suppression of human immunodeficiency virus (HIV) replication by CD8+ T-cells (CD8 suppression) contributes to survival in adults and children < 1 year. Soluble CD8 suppression can also be seen in some older children with AIDS. The factor responsible, CD8-derived antiviral factor (CAF), acts at the level of HIV RNA transcription. Differential gene expression techniques have been used to define the gene(s) mediating this phenomenon in adults. Recently, CAF has been linked to exosomes secreted by CD8+ T-cells. Objective: To compare the gene expression profiles from pediatric patients with each other, with those reported in adults and in those reportedly related to exosomes. Design/Methods: We used differential gene expression to study 3 older children with HIV infection, 1 who did demonstrate soluble CD-8 suppression and 2 who did not, and compared our results with those reported in 2 previous studies in adults and their relatedness to exosome components secreted by CD8+ T-cells. Results: 18 differentially expressed genes were also seen in 1 adult study (p=0.002, Ï2 test), and 38 such genes (p < 0.0001, Ï2 test) in a second adult study. In addition, two exosome components and some RNAâs related to exosomal proteins were also differentially expressed. Conclusions: In children with HIV infection, we found significant differentially expressed genes that correlated to those previously reported in 2 studies in adults. Our data also lends some support to the recent identification of CAF with exosomes secreted by CD8+ T-cells. Differential gene expression was used to study 3 older children with HIV infection, 1 who did demonstrate soluble CD-8 suppression and 2 who did not, and compared our results with those reported in 2 previous studies in adults and their relatedness to exosome components secreted by CD8+ T-cells. Three vertically-HIV-1-infected adolescent boys were studied. This study was approved by the Childrenâs Memorial Institutional Review Board. After informed consent was obtained, 20 - 40 ml of heparinized peripheral blood was collected in association with regularly scheduled, clinically-indicated blood sampling. Keywords: differential gene expression; soluble CD8 suppression; gene array; pediatric HIV infection; CD8-derived antiviral factor

Dataset Information

Exosomal proteomic profiling revealed children type 1 diabete pathogenesis and potential therapeutic targets

Publications

Pathological mechanisms of type 1 diabetes in children: investigation of the exosomal protein expression profile.

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