Leading the way to a cure

2012 FGMP Grants

Functional Genomics and Molecular Pathways in SLE*

This grant mechanism was designed to help researchers move forward from the knowledge gained from the findings of the ALR-funded SLE Genetics Consortium (SLEGEN). Selected investigators receive Research Grants of up to $350,000 for two years or Pilot Grants of up to $75,000 for one year. Grantees will focus on determining how the genes identified by SLEGEN may have a role in the disease, and provide further information about the molecular pathways modulated by these genes. Ultimately, the hope is that data from these investigations will lay the groundwork for a way to "turn off" the disease at the genetic level.

John Atkinson, MD

Washington University School of Medicine<< view more >>
Complement Mutations in End Stage Renal Disease Lupus Patients

With this grant, Dr. Atkinson and two colleagues (Drs. Jane Salmon and Robert Kimberly) are combining forces to determine how genetic variations in complement system genes contribute to kidney disease in people with lupus.

The complement cascade is an important part of the immune system. It helps the host to clear away pathogens like viruses and bacteria as well as damaged tissues and cells. Deficiencies in the complement system lead to lupus and contribute especially to kidney disease.

The researchers will identify variants or mutations in genes of the complement system to see how they contribute to the disease process in lupus.

They will focus on genetic variants that may be involved in lupus-related end-stage renal disease (ESRD) in which the kidneys fail and individuals require dialysis or a kidney transplant. To do this, they will sequence genes in people with lupus-related ESRD; in those with lupus but who do not have kidney disease; and in a group of normal controls. They have two primary goals:

  • Establish that mutations in the complement system increase the risk of ESRD in people with lupus
  • Determine the frequency of the genetic variants in people with lupus compared to controls
What this study means for people with lupus: Identifying genetic variants that contribute to kidney damage in people with lupus will increase our knowledge of how lupus comes about and suggest alternative means to treat the disease.

Richard Bucala, MD

Yale University<< view more >>
Function of the Polymorphic MIF Locus in SLE

Dr. Bucala and his team have identified common variants, or genetic differences between people with and without lupus, of the gene for the immune regulator, macrophage migration inhibitory factor (MIF). This protein directly contributes to the severe, organ-damaging manifestations of lupus. Dr. Bucala and his team have developed new therapies directed at MIF that recently entered clinical testing for lupus nephritis, a development made possible with a previous ALR grant. Nonetheless, learning more about how the MIF gene functions will enable researchers to improve the effectiveness of these and other treatments.

With their new grant, Dr. Bucala and his team will investigate how the MIF influences the function of the autoantibody-producing B lymphocytes that cause lupus. Their goal is to identify the unique DNA-binding proteins that regulate how variant forms of the MIF gene function.

What this study means for people with lupus: Providing molecular insight into how MIF gene variants contribute to lupus will accelerate the application of MIF-based drugs and provide the first "personalized medicine" approach to treating lupus patients based on their genetic susceptibility.

Jane H. Buckner, MD

Benaroya Research Institute at Virginia Mason<< view more >>
The Impact of Genetic Variants on B cell Development and Function in SLE

Systemic lupus erythematosus is an autoimmune disorder with a strong genetic component. It is characterized by B cell production of antibodies that inappropriately recognize selftissues. These autoantibodies contribute to lupus pathogenesis.

To understand how autoantibodies develop in lupus, Dr. Buckner and her team are studying sequence variants in B cell genes that have been associated with susceptibility to lupus. They include those that code for the B cell enzyme BLK and the B cell scaffolding protein BANK1.

Dr. Buckner's team found that the sequence variants in the BLK and BANK1 genes are associated with reduced expression of these genes in B cells in healthy individuals and those with lupus. These expression changes are accompanied by alterations in the cells' normal development.

With this grant, Dr. Buckner and her team will investigate how these genetic variants impact normal B cell function and development and contribute to autoantibody production. They will first determine if the BANK1 genetic variants alter the expression of these genes in specific types of B cells, particularly the B cell subpopulations where auto reactive B cells are normally deleted or deactivated.

Second, they will evaluate the impact of each BANK1 variant on signaling through the B cell receptor, or BCR. The BCR signal is important in removing or deactivating auto reactive B cells during the cell's development so they don't develop into abnormal, autoantibody-producing cells.

Finally, Dr. Buckner's team will determine whether the genetic variants in BANK1 specifically lead to the accumulation of B cell subpopulations that harbor auto reactive cells and the development of B cells that produce autoantibodies.

What this study means for people with lupus: These studies will provide an expanded understanding of one of the mechanisms of disease in lupus, the development of autoantibodies, and will help define new targets for diagnosis and treatment.

Jose C. Crispin, MD

Beth Israel Deaconess Medical Center<< view more >>
Mechanisms Through Which Protein Phosphatase 2A (PP2A) Promotes SLE

T lymphocytes are essential immune regulators. That means they work to fine tune immune responses and determine how those responses occur. However, T cells do not function properly in people with systemic lupus erythematosus (SLE). In fact, there is good evidence that T cell defects contribute to the immune system dysfunction that underlies lupus.

One T cell abnormality in people with lupus is increased levels of an enzyme called PP2A. This enzyme plays an important role in regulating certain cellular proteins and, thus, cell functions. These include cellular division, death, and movement, as well as specialized functions such as the secretion of certain proteins. Therefore, faulty regulation of PP2A levels could, theoretically, contribute to lupus.

In order to determine if abnormally high expression of PP2A can independently contribute to lupus, Dr. Crispin and his group studied animal models that enabled them to show that high levels of PP2A increase susceptibility to kidney inflammation, a common problem in lupus. Further investigation revealed that high PP2A levels enable cells to produce abnormal amounts of a pro-inflammatory molecule called IL-17. Importantly, T cells from people with lupus also produce high levels of IL-17. Thus, the study confirmed that high levels of PP2A can independently contribute to the development of lupus.

With their grant, Dr. Crispin and his team will determine just how high PP2A levels contribute to autoimmunity. They will do this by studying the regulation of the IL-17 gene to better understand how PP2A regulates it. They will then learn how PP2A affects the generation of regulatory cells, which normally curb the inflammatory, IL-17-producing cells.

What this study means for people with lupus: This work will determine the molecular pathways that link a known defect in the T cells of people with lupus with the development of organ damage. A better understanding of this process will help identify better targets for future therapies.

Lindsey Criswell, MD

University of California, San Francisco<< view more >>
Functional Genomics and Pathway Analysis of the MCH Region in SLE

Dr. Criswell and her collaborators will use a large database of DNA, blood and other biospecimens, as well as genetic and clinical data, from more than 15,000 individuals to link genetic variants with key clinical aspects and biomarkers in those with lupus. One goal of the work is to transform current understanding of the major histocompatibility complex (MHC) region on genes and its relationship with non-MHC lupus genes to better understand how the MHC contributes to the disease. Major histocompatibility complex molecules are involved in immune responses as well as autoimmunity.

Specifically, the researchers will:

  • Identify MHC region variants most likely to be related to lupus by sequencing DNA data from 3,800 individuals with lupus and comparing it with DNA from 12,000 individuals without the disease
  • Identify complex molecular networks and cellular pathways for MHC and non-MHC variants involved in disease susceptibility and expression
  • Perform DNA methylation and gene expression studies of MHC variants in lupus. To do this, they will recruit 200 additional patients who were diagnosed with the disease less than 5 years ago, and 200 individuals without lupus.
What this study means for people with lupus: A greater understanding of the genetic contributions to lupus will help identify new pathways for prevention and treatment approaches.

Yanick Crow, PhD

University of Manchester<< view more >>
Pathways Linking Tartrate-Resistant Acid Phosphatase, Interferon, and Lupus

Dr. Crow and his team recently demonstrated that people with changes in the ACP5 gene have a very high risk of developing lupus. These patients also show elevated blood levels of interferon, an inflammatory molecule thought to contribute to the damaging effects of lupus on various parts of the body. High levels of interferon are a sign of lupus in many patients. ACP5 codes for a protein called tartrate resistant acid phosphatase (TRAP). These findings suggest a role for TRAP in the development of lupus by altering control of interferon.

There is some evidence that people with mutations in ACP5 also have higher blood levels of a protein called osteopontin, which is expressed in bone and regulated, in part, by TRAP. Osteopontin appears to play a role in the production of interferon. This finding raises the possibility that TRAP deactivates osteopontin, and that a failure of this deactivation results in an inappropriate up-regulation of interferon.

With their grant, Dr. Crow and his collaborator Keith Elkon, MD, from the University of Washington, will investigate how TRAP expression is regulated in human immune cells, concentrating particularly on the relationship between TRAP, osteopontin and type I IFN stimulation.

What this study means for people with lupus: A better understanding of the role of TRAP in interferon metabolism could help to identify new treatment targets for lupus.

Yun Deng, MD

University of California, Los Angeles<< view more >>
Does Differential miRNA Binding Explain Allelic Risk of TLR7 for SLE

Recent evidence suggests the importance of innate immunity in the development of systemic lupus erythematosus. The toll-like receptor 7 (TLR7), which helps guide responses against self antigens and activates the inflammatory type I interferon (IFN) pathway, plays a pivotal role in the disease’s development.

An earlier study from Dr. Deng's laboratory confirmed a variant form of the TLR7 gene that is associated with lupus. This mutation results in higher TLR7 expression and a more robust type IFN-1 signature, both of which are implicated in the development of lupus.

MicroRNAs (miRNAs) have emerged as important regulators of gene expression. Mutations in miRNA target sites can affect their regulatory roles, thus affecting cellular function. One question Dr. Deng and her team will explore is the role of miRNAs in regulating TLR7 expression. They will focus on whether the miRNAs thought to target the TLR7 gene at and around the location of the identified mutation could lead to changes in the expression of TLR7 and other IFN-related genes.

What this study means for people with lupus: This project will help identify the molecular mechanism underlying the variant form of the TLR7 gene, implicate an important role of specific miRNA in regulating TLR7signaling, and may lead to the potential application of miRNA-based targeted therapy in lupus.

Di Feng, PhD

UMDNJ-New Jersey Medical School<< view more >>
Identifying IRF5-Mediated Pathways In Normal And SLE B Cells

Numerous genes, proteins and enzymes are involved in the underlying dysfunction of lupus. One such protein is interferon regulatory factor 5 (IRF5). This protein regulates key pro-inflammatory molecules, or cytokines, such as interferon alpha (IFN-a), interleukin (IL) IL-6, IL-12, and tumor necrosis factor alpha (TNF-a), which are elevated in people with lupus.

However, little is known about the contribution of IRF5 to the development of human lupus. Based on murine studies, it is thought that IRF5 may play a role in the B cell dysfunction of lupus by affecting B cell activation, proliferation, differentiation, autoantibody production, and cytokine expression, among other processes.

With their grant, Dr. Feng and his team will explore two key questions: What is the essential function of IRF5 in human B cells, and how does IRF5 influence the ability of B cells to produce the destructive autoantibodies that are the hallmark of lupus?

What this study means for people with lupus: Results from this study will determine how IRF5 contributes to lupusrelated B cell dysfunction. A greater understanding of the role of this protein can provide new targets for treatment.

Peter K. Gregersen, MD

Feinstein Institute for Medical Research<< view more >>
Functional Analysis of Csk: A Newly Defined Risk Gene for Lupus

In recent years, researchers, many of them funded by the Alliance for Lupus Research, have identified a plethora of genes and genetic variants likely responsible for the dysfunctional immune responses that underlies lupus.

Dr. Gregersen and his team identified one such gene, Csk, which is directly involved in setting the threshold for immune cell activation, or their "call to action." It is also associated with several other autoimmune disorders, including scleroderma and celiac disease.

The team has found a particular genetic variation in this gene that influences how much of the Csk protein is produced, particularly in B cells, which produce the autoantibodies that are the hallmark of lupus. The team also showed that the amount of Csk in B cells, particularly B cells early in their development, have a profound effect on the number of these cells and their ability to be activated. They have also found that Csk interacts with other known risk genes for lupus, including Lyn and PTPN22.

With their grant, Dr. Gregersen and his team will explore further the role Csk plays in B cell aberrations and the development of lupus.

What this study means for people with lupus: A better understanding of the role of Cskin B cell regulation and the development of lupus could help identify new approaches to therapy or even opportunities to manipulate B cells early in their development so they can’t contribute to the development of autoimmune diseases like lupus.

Terry K. Means, PhD

Massachusetts General Hospital<< view more >>
In Vivo Validation And Characterization Of Allelic Variants In Lupus

Genome-wide association studies such as the SLE Genetics consortium have identified numerous genetic variants associated with an increased risk of lupus. However, a major barrier in lupus research is the lack of a rapid high-throughput system, a special kind of technology that can validate these candidate variants and determine if they truly do contribute to lupus.

Dr. Means and his team have developed and optimized a novel approach to express human, lupus-related genes in animal models. This approach can rapidly generate animal models that harbor an immune system developed with cells that express human genetic mutations.

With this grant, the team will use their animal models to study the effects of human lupus-related risk genes on the development and progression of lupus.

What this study means for people with lupus: These studies will provide a rich pipeline of molecular targets that could be fast-tracked for the development of lupus-related treatments.

Derry Roopenian, PhD

The Jackson Laboratory<< view more >>
Novel Approach to Modeling the Functional Genomics of Human LE in Mice

Like most autoimmune syndromes, the genetic predisposition to lupus is complex. We see this complexity in genetic association studies that have identified anomalies in more than 30 genes that provide small, but significant, contributions to the disease. However, only when several of these genetic variations occur simultaneously does the disease itself result. Thus, it is difficult to translate these complex genetic patterns into a biological explanation of the specific anomalies that cause lupus, and even more challenging to apply this information to benefit people with lupus.

With their grant, Dr. Roopenian and his team will use a mouse model to explore these issues. They will mimic the genetic changes seen in humans with lupus in the mouse and observe the results of such abnormalities. They will combine this information with gene expression studies to discover the molecular pathways that determine susceptibility and resistance to lupus in mice.

What this study means for people with lupus: Conducting studies in mice to specifically address genes we already know affect the risk of lupus in humans should provide important information for predicting, understanding, and treating lupus and related disorders in humans.

Anne Satterthwaite, PhD

University of Texas Southwestern Medical Center<< view more >>
Functional Relationships Between the Lupus Susceptibility Loci Lyn and Ets1

A key contributor to lupus is the production of antibodies that recognize the body's own components (autoantibodies). These antibodies, which are produced from B cell-derived plasma cells, collect in various tissues and organs, including the kidney, causing inflammation and tissue damage.

Two genes involved in the development of lupus, Lyn and Ets1, limit production of these plasma cells in mice. Without either of those genes, mice develop a lupus-like autoimmune disease. Dr. Satterthwaite, her colleague Lee Ann Garrett-Sinha, PhD, and their teams have shown that B cells that lack Lyn also have reduced Ets1 levels, suggesting that the two genes operate in a common pathway to control the development of plasma cells and the production of autoantibodies.

With their grant, they will test the hypothesis that Lyn normally prevents autoantibody production by promoting the expression of the Ets1 protein. Among the questions they will explore:

  • Does Lyn act in B cells or some other cell type to control Ets1 expression?
  • Which pathways regulated by Lyn are involved in altering Ets1 expression?
  • Does Lyn control the expression of the Ets1 gene or regulate the stability of the Ets1 protein?
They will also explore the consequences of reduced Ets1 levels in Lyn-deficient B cells, and determine whether low levels of Lyn and Ets1 together contribute to the development of autoimmunity. They will also restore normal Ets1 levels in Lyn-deficient B cells to see if this prevents autoantibody production.

What this study means for people with lupus: Defining and characterizing this novel pathway may reveal new therapeutic targets that could prevent the antibody-related tissue damage.

Katherine Siminovitch, MD

University Health Network<< view more >>
Defining Functional Implications of a Human SLE Risk Allele in Mice

Among the many genes now shown to contribute to the development of lupus is PTPN22, a gene that codes for a tyrosine phosphatase called Lyp. Lyp is found only in blood cells and is important for suppressing T lymphocyte activity. Many people with lupus express a variant form of Lyp called Lyp620W. However, we don’t know how this variant contributes to the disease process.

With this grant, Dr. Siminovitch and her team hope to identify the pathways that link the Lyp620W variant to risk for lupus. To do so, they will study mice that express this variant. Initial work with these animals found numerous immune cell defects, particularly, "hyper" activation of T and B lymphocytes. Analysis of these mice also revealed that the variant protein is unstable and is broken down too quickly, resulting in very low levels in the mouse lymphocytes. The team then showed that these abnormalities also occur in cells from humans expressing the Lyp620 variant. These findings suggest that the PTPN22 gene variant causes reduction in Lyp levels and in the ability of Lyp to suppress immune cell activation. The result is immune cell hyperactivity.

Dr. Siminovitch and her team will now further define the Lyp variant's effects on T and B cell functions, particularly activation, movement, and development. For instance, they will compare how cells from mutant and normal mice divide or migrate in response to select stimuli, and examine the cells' secretion of inflammatory cytokines involved in autoimmune responses.

They will also study T and B lymphocyte development in the mouse model to assess whether the variant alters early elimination of autoreactive cells, which occurs in people with normal immune systems, but may be reduced in those with lupus.

Another set of studies will define the variant protein's effects on autoimmunity and how this genetic variant interacts with other genetic variants to cause lupus.

What this study means for people with lupus: Defining the pathways related to a specific genetic variant could identify new targets for treatment.

William Tansey, PhD

Vanderbilt University Medical Center<< view more >>
Characterization Of PHRF1; A Ubiquitin Ligase Implicated In SLE

Effective strategies to prevent, diagnose, treat, and cure lupus will ultimately be based on a detailed understanding of the genetic pathways involved in the disease. Over the past 15 years, researchers have made great strides in identifying genes that increase the risk of lupus, but there is still a great deal of work required to understand the function of these genes and their role in the disease.

Dr. Tansey's work centers on a gene called PHRF1, thought to be involved in lupus. However, there is little understanding of how the gene functions or of its contribution to the disease.

Dr. Tansey and his team have identified versions of PHRF1 and learned that these genes display characteristics that suggest some relevance to lupus. Because related genes from other species often show identical behavior, they hypothesize that the human version of PHRF1 shares these same molecular functions.

With their grant, the team will study the other versions of PHRF1, particularly with respect to how they control gene expression relevant to immunity and other lupus-related events.

What this study means for people with lupus: These studies will provide much-needed information that will allow researchers to assess the molecular contribution of PHRF1 to lupus. The results of these and other studies will eventually enable researchers to design diagnostic or therapeutic strategies based on PHRF1that could help diagnose lupus early and/or treat and prevent it.

Betty Tsao, PhD

University of California, Los Angeles<< view more >>
Functional Genomics of SLE-associated SMG7/NMNAT2 Locus

Genome-wide association studies (GWAS) have greatly expanded our understanding about genetic variants linked to the risk of lupus. However, simply knowing the link between a genetic variant and lupus is just the first part of a story. Far more important, however, is understanding how that genetic variant affects the immune system and results in lupus.

With this grant, Dr. Tsao and her team will explore the underlying mechanism of the newly identified NMNAT2/ SMG7 risk locus, an "address" of two neighboring genes, to better understand its role in lupus.

The NMNAT2 gene regulates energy metabolism, primarily in the brain, but its role in lupus is unclear. In contrast, SMG7 serves as a "cleaner" in cells, controlling mRNA quality, gene expression and alternative splicing, which are important for the production of autoantibodies in lupus.

Earlier studies showed a link between lupus-associated SMG7 variants and reduced expression of SMG7, while decreased SMG7 levels appear to lead to elevated production of antinuclear autoantibodies, the most prevalent autoantibodies in lupus.

These studies will focus on whether dysfunction in messenger RNA surveillance systems resulting from the lupus-associated SMG7 variants may be a unique mechanism contributing to the development of lupus.

What this study means for people with lupus: Greater understanding of the underlying pathology of lupus—what goes wrong at the cellular and molecular level—will enable the development of treatments that target those abnormalities.

*We are currently not funding any new grants under the Functional Genomics and Molecular Pathways in SLE mechanism.

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