Project Details
Abstract
Glomerulonephritis (GN), characterized by inflammation either of the glomeruli or small blood
vessels in the kidneys, may result from autoimmunity directly against renal specific antigens or an
aberrant systemic immune response. Hence, for those suffering autoimmune renal diseases, immune
tolerance may be the billion-dollar answer to their challenge.
Regulatory T cells (Treg) play a crucial role in the immune microenvironment by limiting the
immune responses. T follicular helper (Tfh) lineage, an effector CD4(+) T cells characterized by the
production of IL-21, play crucial role in the selection of high affinity B cells to drive antibody or
autoantibody formation. According to our preliminary data, hypoxia-inducible factor 1 (HIF-1)
involves Treg degradation and miR17-92 production in mitigating Treg function. In addition,
miR17-92 augments Tfh development. Given that the HIF-1 plays a critical role in Treg and Tfh,
HIF-1 inhibitory compounds may alleviate GN by Treg enhancement and Tfh reduction. We thus
propose a novel therapeutic strategy to rescue GN via HIF-1 inhibition.
How HIF-1 modulates different T cells subsets via epigenetic regulation and the exact mechanism
of how HIF-1 mediates Treg and Tfh dysfunction remain open questions. To begin with, we will
exam the transcriptome and epigenetic profiling regulated by HIF-1 in different CD4 T cell subsets,
especially focusing on the reprogramming of metabolic pathways. An in vivo HIF-1 reporter assay
will be built to evaluate the correlation between HIF-1 activity and the signature molecules (e.g.
Foxp3, Bcl-6) on a single cell basis during Treg and Tfh development in vivo. We will also measure
glycolysis and mitochondrial respiration status to correlate epigenetic profiling mentioned above.
Therefore, we’d be able to associate the metabolic regulations with the development of Treg/Tfh at
different stages. Secondly, Foxp3 co-regulators, such as Eos, IRF4, Gata1, LEF1 and Satb1, are
crucial in Treg suppression function. We will search a panel of miRNAs within the miR17-92
cluster for the ones with the ability to bind the 3’UTR of foxp3 co-regulators by bioinformation. We
then will apply reporter assay to later confirm the results. To further characterize the impact of the
specific miRNA in Treg cells function in vitro, suppression assay for Treg with ectopic expression
and knockdown of miRNA will be done. We also aim to initiate a Treg-dependent colitis model with
ectopic expression of miRNA in Treg to investigate the effect of miRNA for Treg function in vivo,
Finally, We will take advantage of our available HIF-1 inhibitors. A combination of HIF-1 inhibitors
will be given to evaluate the effect of immune tolerance in two GN models, pristane nephropathy
and nephrotoxic nephritis, which stand for GN caused by systemic autoimmunity and renal
antigen-elicited autoimmunity respectively.
In sum, this proposal will be the very first experiment focusing on HIF-1 mediate epigenetic change
in the development of CD4 T cell subsets. Also, we will elucidate the miRNA responsible for Treg
function modulation. We then will screen HIF-1 inhibitors for future clinical applications in GN.
Project IDs
Project ID:PC10701-0337
External Project ID:MOST105-2628-B182-005-MY3
External Project ID:MOST105-2628-B182-005-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/18 → 31/07/19 |
Keywords
- Glomerulonephritis
- Hypoxia inducible factor 1
- Regulatory T cell
- T follicular helper cell
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