Examples of Ongoing Research in the Miner Lab

Why we study rare diseases

Small molecular inhibitor for a rare disease patient
Small molecular inhibitor bound to its target, currently being refined and improved for our rare disease patients.
A major priority for our laboratory is to define mechanisms of rare rheumatic diseases, and to develop and test personalized therapies for those diseases. In particular, we focus our studies on cytosolic nucleic acid-sensing pathways. We currently have active collaborations with multiple investigators to develop personalized medicines for rare diseases. This includes collaborators at multiple institutions around the country.
Rare disease research is important because these diseases are devastating and untreatable.  Many of these patients die prematurely, but their diseases could be cured since they are a consequence of a single gene mutation.  
Studying monogenic diseases also gives insight into fundamental mechanisms of biology and disease. Another benefit of this work is that the pathways targeted are highly relevant for a wide variety of common diseases, including infections, cancer, and autoimmune diseases. Thus, many of the therapies being developed are likely to be of broad utility for common diseases as well.

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Rare disease discovery and mechanisms

cGAS STING pathway Miner et al
Mutations in nucleic acid sensors cause severe autoimmunity.
Our laboratory is currently supported by the National Institutes of Health (NIH), by private foundations, and by rare disease patients, as well as by their friends and families.
Our research is centered on immunological pathways related to nucleic acid sensors that reside in the cytosol.  These pathways play a vital role as he first line of defense against viral infections. Activation of nucleic acid sensors leads to induction of interferons. Mutations in genes that encode nucleic acid sensors can cause autoimmune disease, including a class of diseases known as "interferonopathies." 
Our laboratory merges combined expertise in immunology, rheumatology, and virology to elucidate mechanisms of rare diseases, and to understand how nucleic acid sensors regulate immunity against viruses. Additionally, we are working with collaborators to describe novel diseases related to mutatiions in these pathways. 
We also study how these pathways regulate the response to viral infections, and we work with many different types of viruses in the laboratory, including with Biosafety Level 3 (BSL3) viruses.

Role of TREX1 in RVCL and vasoocclusion

RVCL mutant TREX1
Heterozygous frameshift mutations in the DNAse TREX1 cause a disease called RVCL.  Mislocalization of truncated TREX1 protein dysregulates B cell function and causes endotheliopathy.
RVCL is a rare inherited disease caused by mutations in a gene called TREX1, which is found on chromosome 3. TREX1 is a DNAse that negatively regulates the cGAS-STING pathway, which is one of the cytosolic nucleic acid-sensing pathways that we study in our lab. 
RVCL is inherited in a autosomal dominant pattern, which means that about half of family members are affected. Patients with RVCL have one normal copy of TREX1, and one mutated copy of TREX1.
Normally, the TREX1 protein is attached to a membrane inside the cell.  In patients with RVCL, one copy of TREX1 is abnormally shortened because of the mutation.  This causes the TREX1 protein to float freely in the cell, rather than being anchored to the membrane.  
Mislocalization of the TREX1 protein somehow causes cellular damage and disease. The exact mechanism remains to be defined, but we are working on this.  Additionally, we are working to develop therapies targeting the mutated TREX1 gene and protein.
LRVCL-S / RVCLearn more about RVCL by exploring these links:

Interferon (IFN)-mediated immunity against viruses

IFN pathways
Type I and type III IFN receptors utilize different receptors to activate similar downstream effectors and antiviral IFN-stimulated genes.  The type II IFN receptor also activates IFN-stimulated genes, but via distinct pathways.
We have conducted multiple NIH-funded projects related to interferon (IFN)-mediated immunity against viruses. Several trainees in our laboratory have done work in this area.
This led to multiple publications in Science Translational Medicine, Cell Reports, and Journal of Virology.
Some of our recent discoveries include the identification of the type III interferon receptor (IFN-lambda receptor) in the human cornea, and the discovery that multiple flaviviruses including West Nile virus and Powassan virus can cause congenital infection in model systems.  Additionally, we found that the human cornea does not support growth of SARS-CoV-2 in culture conditions, although that finding does not necessarily indicate that the eye or surrounding tissues would not be a site of initial infection by this virus.

CRISPR/Cas9 screening to identify novel regulators of innate immune pathways

CRISPR Cas9 screen
In whole-genome CRISPR/Cas9 screening, a patient's disease-causing mutant can be expressed in a library of cells.  In each cell, a different host gene has been deleted. At the end of the screen, the only cells that survive are cells resistant to the effect of a patient's mutation.  By identifyhing the deleted gene in the surviving cells, we are able to define novel regulators of the target protein.
A major focus of the work in our laboratory has been to use patients' disease-causing mutations to identify novel regulators of nucleic acid-sensing pathways.  This work has major implications for identifying therapeutic targets.  Additionally, this approach has led us to discover disease-specific regulators of signaling. Studying patient mutations also gives insight into normal biology because it helps to clarify mechanisms by which normal genes and proteins are regulated.

Interferon-mediated regulation of lymph node development

SAVI mice lack lymph nodes
Mice with STING gain-of-function mutations develop SAVI.  We discovered that they also lack lymph nodes. Now we are defining novel mechanisms that regulate lymph node development.
STING gain-of-function mutations cause a severe autoimmune disease in humans. One aim of our NIH-funded research is to define mechanisms of a disease is called STING-associated vasculopathy with onset in infancy.  Constitutive STING signaling leads to induction of interferon-stimulated genes, and this phenomenon is associated with immune dysregulation. 
In mice that have SAVI mutations, innate lymphoid cells and lymph nodes fail to develop.
This work revelaed a novel contribution of aberrant STING signaling in dysregulating innate lymphoid cell development. We are now investigating the role of STING, interferons, and chemokines during lymph node development in mice.

You can hear more about our work here:
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