Matching Items (3)

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Exploring genetic associations with ceRNA regulation in the human genome

Description

Competing endogenous RNAs (ceRNAs) are RNA molecules that sequester shared microRNAs (miRNAs) thereby affecting the expression of other targets of the miRNAs. Whether genetic variants in ceRNA can affect its

Competing endogenous RNAs (ceRNAs) are RNA molecules that sequester shared microRNAs (miRNAs) thereby affecting the expression of other targets of the miRNAs. Whether genetic variants in ceRNA can affect its biological function and disease development is still an open question. Here we identified a large number of genetic variants that are associated with ceRNA's function using Geuvaids RNA-seq data for 462 individuals from the 1000 Genomes Project. We call these loci competing endogenous RNA expression quantitative trait loci or ‘cerQTL’, and found that a large number of them were unexplored in conventional eQTL mapping. We identified many cerQTLs that have undergone recent positive selection in different human populations, and showed that single nucleotide polymorphisms in gene 3΄UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in both cis and trans by the ceRNA mechanism. We also discovered that cerQTLs are significantly enriched in traits/diseases associated variants reported from genome-wide association studies in the miRNA binding sites, suggesting that disease susceptibilities could be attributed to ceRNA regulation. Further in vitro functional experiments demonstrated that a cerQTL rs11540855 can regulate ceRNA function. These results provide a comprehensive catalog of functional non-coding regulatory variants that may be responsible for ceRNA crosstalk at the post-transcriptional level.

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Agent

Created

Date Created
  • 2017-05-02

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Activation of E-prostanoid 3 receptor in macrophages facilitates cardiac healing after myocardial infarction

Description

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6C[superscript low] and Ly6C[superscript high]) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E[subscript 2] is involved in the Mo/Mp-mediated inflammatory response,

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6C[superscript low] and Ly6C[superscript high]) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E[subscript 2] is involved in the Mo/Mp-mediated inflammatory response, however, the role of its receptors in Mos/Mps in cardiac healing remains to be determined. Here we show that pharmacological inhibition or gene ablation of the Ep3 receptor in mice suppresses accumulation of Ly6C[superscript low] Mos/Mps in infarcted hearts. Ep3 deletion in Mos/Mps markedly attenuates healing after MI by reducing neovascularization in peri-infarct zones. Ep3 deficiency diminishes CX3C chemokine receptor 1 (CX3CR1) expression and vascular endothelial growth factor (VEGF) secretion in Mos/Mps by suppressing TGFβ1 signalling and subsequently inhibits Ly6C[superscript low] Mos/Mps migration and angiogenesis. Targeted overexpression of Ep3 receptors in Mos/Mps improves wound healing by enhancing angiogenesis. Thus, the PGE[subscript 2]/Ep3 axis promotes cardiac healing after MI by activating reparative Ly6C[superscript low] Mos/Mps, indicating that Ep3 receptor activation may be a promising therapeutic target for acute MI.

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Agent

Created

Date Created
  • 2017-03-03

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Frameshift antigens for cancer vaccine development

Description

Immunotherapy has been revitalized with the advent of immune checkpoint blockade

treatments, and neo-antigens are the targets of immune system in cancer patients who

respond to the treatments. The cancer vaccine field

Immunotherapy has been revitalized with the advent of immune checkpoint blockade

treatments, and neo-antigens are the targets of immune system in cancer patients who

respond to the treatments. The cancer vaccine field is focused on using neo-antigens from

unique point mutations of genomic sequence in the cancer patient for making

personalized cancer vaccines. However, we choose a different path to find frameshift

neo-antigens at the mRNA level and develop broadly effective cancer vaccines based on

frameshift antigens.

In this dissertation, I have summarized and characterized all the potential frameshift

antigens from microsatellite regions in human, dog and mouse. A list of frameshift

antigens was validated by PCR in tumor samples and the mutation rate was calculated for

one candidate – SEC62. I develop a method to screen the antibody response against

frameshift antigens in human and dog cancer patients by using frameshift peptide arrays.

Frameshift antigens selected by positive antibody response in cancer patients or by MHC

predictions show protection in different mouse tumor models. A dog version of the

cancer vaccine based on frameshift antigens was developed and tested in a small safety

trial. The results demonstrate that the vaccine is safe and it can induce strong B and T cell

immune responses. Further, I built the human exon junction frameshift database which

includes all possible frameshift antigens from mis-splicing events in exon junctions, and I

develop a method to find potential frameshift antigens from large cancer

immunosignature dataset with these databases. In addition, I test the idea of ‘early cancer

diagnosis, early treatment’ in a transgenic mouse cancer model. The results show that

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early treatment gives significantly better protection than late treatment and the correct

time point for treatment is crucial to give the best clinical benefit. A model for early

treatment is developed with these results.

Frameshift neo-antigens from microsatellite regions and mis-splicing events are

abundant at mRNA level and they are better antigens than neo-antigens from point

mutations in the genomic sequences of cancer patients in terms of high immunogenicity,

low probability to cause autoimmune diseases and low cost to develop a broadly effective

vaccine. This dissertation demonstrates the feasibility of using frameshift antigens for

cancer vaccine development.

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Agent

Created

Date Created
  • 2018