The National Scleroderma Foundation has proudly awarded more than $34 million in scleroderma research grants. These projects received the Peer‑Review committee’s highest ranking for scientific design quality and the prospect of advancing the scleroderma body of knowledge.
Because grants are spread over two or three years, in any given year, the Foundation has funding commitments to more than two dozen ongoing projects. Our commitment to these projects is a driving force behind fundraising efforts such as Stepping Out to Cure Scleroderma walks.
Mechanistic connections between NETs and scleroderma vasculopathy University of Michigan
New Investigator Award
Systemic sclerosis (also called scleroderma) is an autoimmune disease that impacts the skin and internal organs such as the lungs, heart, kidneys, and gastrointestinal tract. It is characterized by widespread thickening and tightening of the skin, progressive blood vessel damage, and abnormal immune activation. There is an unmet need for more effective and more precise therapies. Neutrophils are potentially destructive white blood cells that release toxic products called neutrophil extracellular traps (NETs), sticky webs of DNA and proteins that have been shown to play a critical role in various autoimmune diseases. However, the role of neutrophils and NETs in scleroderma remains significantly understudied. Here, we propose to investigate how a deep understanding of neutrophils and NETs in systemic sclerosis may guide therapeutic decisions in early stages of the disease, especially in patients at risk for vascular complications such as finger ulcers and pulmonary hypertension. We will use banked blood samples and fresh blood from hospitalized patients to identify novel targets for neutrophil modulation, as well as to characterize mechanistic connections between NETs and the clinical manifestation of scleroderma. Neutrophils and NETs are important mediators of scleroderma-associated vascular disease, and anti-NET therapeutics might be a potential approach to reduce their impact on scleroderma.
Brendon Baker, PhD
Debra Lurvey Memorial Grant Award
Metabolic and epigenetic targeting of stromal cell-matrix crosstalk for reversing fibrosis in scleroderma University of Michigan Established Investigator Award
Systemic sclerosis (SSc) is a chronic and incurable disease characterized by fibrosis of the skin, lungs, and other internal organs. Previous research has focused on scar-forming cells called myofibroblasts (MFs) that cause lung dysfunction, respiratory failure, and eventually death. However, recent work has implicated additional stromal cell (ie. resident endothelial cells and fibroblasts) in fibrotic diseases across numerous organ systems. Separately, other studies have highlighted metabolic and epigenetic reprogramming in stromal cells during cancer-associated fibrosis and identified a potential therapeutic target in the form of nicotinamide Nmethyltransferase (NNMT) that dually regulates metabolism and epigenetics. Using our patented first-in-class NNMT inhibitors, this work aims to employ bioengineered microphysiologic co-culture models to examine the effect of NNMT inhibition on disease driving cellular crosstalk and key cellular processes involved in cell and tissue dysregulation. These studies will provide key data motivating future animal studies needed to move our novel compound towards the clinic in addition to mechanistic insight into its mode of action, both critical to developing effective therapies for SSc patients.
Md Nurunnabi, PhD
Investigating nanoparticle enabled cell specific apoptosis induction and fibrosis treatment The University of Texas at El Paso New Investigator Award
Scleroderma or systemic sclerosis (SSc) is one of the autoimmune rare diseases diagnosed withing a diverse community regardless of age, gender, and race but pre-dominant within the female population ages between 25 to 55. Despite of significant improvement of medical science, there is very limited, yet not very effective treatment options to treat scleroderma pathologically. Our goal in this project is to investigate a group of potent therapeutic molecules that has been shown to be effective in treating scleroderma more efficiently. Scleroderma is characterized by excessive deposition of collagen and other proteins which induce stiffness to the tissue and cause various physiological problems. For instance, scleroderma in lung cause breathing problem due to constriction of air-vessel, cause blood pressure due to constriction in blood vessel. Scleroderma in skin usually causes sores and scars which further induce severe pains in the joins of fingers. Fibroblast is a type of cell is responsible for producing excessive amount of collagen within the organ when they are inflamed and irritated by the toxin known as cytokines such as TGF-ß. Therefore, we envision that inhibition of pathways that are responsible, can help to treat or reverse the diseases pathologies. When a fibroblast is inflamed and insulted by cytokines, they convert to a cell type that produces collagen excessively, and these cells are defined as myofibroblast. However, the therapeutic candidates have also potential to induce toxicity when they are accumulated by the healthy and unwanted cells including endothelial, epithelial, and immune cells. Therefore, it is very important to control and regulate the uptake and accumulation of the therapeutic drugs by the cells of interest. This project is designed to develop a nano-formulation for specific delivery of Bcl-2/Bcl-xL inhibitors to dermal myofibroblasts to increase specificity and therapeutic efficacy by controlling random accumulation. With development of such myofibroblast specific Bcl-2/Bcl-xL inhibitor, we envision to improve scleroderma treatment in skin. Therefore, in this proposal we will consider to most potent inhibitors that concurrent and equally effective of inhibiting both Bcl-2 and Bcl-xL proteins.
Mohammed Osman, MD, PhD
Evaluating a role for polysialic acid as a diagnostic, prognostic and therapeutic target in systemic sclerosis University of Alberta Established Investigator Award
Scleroderma is a life-threatening inflammatory disease that affects ~44/100,000 people in North America. The current treatment options for patients with scleroderma are limited, largely because we do not understand the mechanisms underpinning the disease (particularly early in the disease), and there is an absence of biomarkers linked to the disease which can predict how the disease can affect people over time. Our team has identified a sugar (or glycan) which is present in the skin of people with scleroderma and completely absent from healthy controls. This glycan, called polysialic acid, is normally found in healthy tissues in the immune, nervous, and reproductive systems where is helps cells migrate to places they need to go and also helps turn down the immune system. Because polysialic acid is not normally present in healthy skin cells but found in all patients with scleroderma that we’ve tested, we hypothesize that polysialic acid plays a role in the development and progression of scleroderma and fibrosis. Additionally, we predict that we may be able to use the presence of polysialic acid as a biomarker which can identify people with scleroderma and possibly the severity of their disease. By the end of this proposal, we expect to have generated foundational data linking polysialic acid to fibrosis in the skin and lungs of scleroderma patients; and strong data showing that it is both a diagnostic and prognostic biomarker.
Reshmi Parameswaran, MS, PhD
BAFF CAR-T treatment for systemic sclerosis Case Western Reserve University Established Investigator Award
This proposal describes a novel chimeric antigen receptor (CAR)-T cell therapy that aims to improve outcomes for patients with systemic scleroderma (SSc). Our approach improves upon current immunotherapies by engineering T cells in a unique way to express a novel CAR directed against inflammatory cytokine and autoantibody producing B cells. We expect immunotherapeutic delivery of these modified T cells will improve patient outcomes and reduce long-term pathology by reducing inflammation and increasing safety.
Laura Polivka, MD, PhD
Marta Marx Fund for the Eradication of Scleroderma Award
Exploring the pathogenesis of severe juvenile systemic sclerosis Kao Autoimmunity Institute Cedars-Sinai Medical Center New Investigator Award
The mechanisms of development of systemic sclerosis (SSc) are still poorly understood and to date there is no treatment to cure SSc. Although SSc mainly affects women aged between 40 and 50 it can also affect children. We are focusing on rare SSc forms in children for which a genetic origin is probable as we believe that understanding their mechanism not only can help improve management of disease in the affected children but also in adult SSc. Here we studied 3 patients who presented with very severe juvenile SSc. Genetic analysis identified a mutation in a gene coding for a molecule whose function and structure are almost completely unexplored. Our hypothesis is that this molecule plays a crucial role in the mechanism of this very severe juvenile SSc subtype. Here we will carry out the initial work needed to confirm that this molecule is involved in the mechanism of disease. In subsequent explorations we hope we will understand also how the molecule could be targeted to prevent or reverse disease. We hope that the knowledge gained not only will help other unfortunate children affected by severe juvenile SSc but also help discover new therapeutic targets for adult forms of SSc.
Maria Teves, PhD
Walter and Marie Coyle Award
Advancing scleroderma treatment: a study using primary cilia as a therapeutic target
Virginia Commonwealth University Established Investigator Award
Systemic sclerosis (SSc) is a devastating chronic fibrotic disease with no effective treatment. While several factors have been implicated in the pathogenesis of SSc, the underlying molecular mechanisms remain poorly understood. Our goal is to unravel the mechanisms driving fibrosis and discover novel therapeutic strategies. In this quest, we turn our attention to the primary cilium (PC), a specialized cellular organelle that regulates molecular signaling. Remarkably, we have recently uncovered compelling evidence connecting PC with SSc pathophysiology. Our groundbreaking investigations have revealed significant alterations in PC and PC-associated genes in skin biopsies from SSc patients. Moreover, we have demonstrated that the activation of profibrotic signaling can be induced both in vivo and in vitro by genetic ablation of cilia-associated genes and/or exposure to pharmacological compounds that injure PC. Building on this critical evidence, we aim to investigate PC as a novel therapeutic target for SSc. Our innovative research will serve as a foundation for the development of advanced treatments and will shape the basis for future clinical advancements in the field. This visionary pursuit of knowledge is poised to make a lasting impact on the lives of SSc patients, leading in an era of hope, healing, and renewed possibilities.
The Marta Marx Fund for the Eradication of Scleroderma
Centromeres, Chromosome Instability, and cGAS-STING Activation in Scleroderma Fibrosis University of Minnesota
Established Investigator Award
Patients with scleroderma produce antibodies that interact with chromosomes, microscopic thread-like structures inside our cells that carry genetic information. Specifically, the antibodies recognize the centromere, the middle region of each chromosome. The centromere is very important to cells, as it is the location at which chromosomes are pulled apart to be equally divided to daughter cells during cellular division. Defects in centromeres can lead to unequal distribution of chromosomes, creating cells with incomplete genetic information that can become diseased. Although scleroderma patients have antibodies that bind centromeres, it remains unclear whether centromeres and chromosomes function properly in scleroderma patients. We have seen that skin fibroblasts, the type of cell that thickens the skin in scleroderma lesions, have centromere defects and have abnormal chromosomes. Importantly, chromosome abnormalities activate genes that trigger inflammation and fibrosis. This project will investigate the role of centromere and chromosome defects seen in scleroderma patients in the development of skin and other organ lesions. We will evaluate the effect of drugs that target chromosome defects to alleviate fibrosis and inflammation. Understanding how healthy skin cells turn into skin lesions is important to ascertaining the cause of scleroderma and to finding a cure to treat this devastating disease.
Roxane Darbousset, PhD
Mark Flapan Award
Platelets as Driver of NET Formation in Systemic Sclerosis Boston Children’s Hospital
New Investigator Award
Systemic sclerosis (SSc) is a disabling autoimmune disease characterized by excessive scarring and progressive loss of organ function. SSc generally occurs in the skin but can also extend to vital internal organs including the lung. The mechanisms that drive this process remain poorly understood. Recent studies suggested that two kinds of blood cells, neutrophils, and platelets, contribute to the development of SSc. We studied SSc in mouse models and found that neutrophils are activated during the disease progression, and that neutrophil depletion attenuated the extent of SSc. We found that platelets, also activated in SSc, possess the capacity to promote neutrophil activation and are associated with neutrophil extracellular trap (NET) formation, which is the release of DNA by highly activated/dying neutrophils. NETs are important potentiators for the scarring process. Intriguingly, we identified a new way that neutrophils and platelets interact: transfer of mitochondria from platelets to neutrophils. Mitochondria are organelles that generate metabolic energy, suggesting that mitochondrial transfer could help to enhance neutrophil activation. In this project, we will test the hypothesis that platelet mitochondrial transfer could be associated with NET formation during SSc. Ultimately, understanding plateletneutrophil synergy may help identify new ways to treat SSc.
Justin Lui, MD
Walter & Marie Coyle Research Grant
Cardiac Strain Phenotyping of Systemic Sclerosis-related Pulmonary Hypertension Boston University
New Investigator Award
Pulmonary hypertension is a condition caused by high pressure in the blood vessels that connect the heart and the lungs. It affects about 1 in 10 patients with systemic sclerosis and is a major cause of death in these patients. Many patients with pulmonary hypertension have signs of heart disease from systemic sclerosis, which may explain why these patients do so poorly. In this project, we will study how abnormalities in the way the heart squeezes and relaxes are related to increased scarring in the heart and poorer clinical outcomes.
Natalie Saini, MSc, PhD
Cogan Family Research Grant
Determining the Somatic Mutation Burden and it’s Consequences in Scleroderma-lung Disease Medical University of South Carolina
Established Investigator Award
Systemic sclerosis (SSc) associated interstitial lung disease (ILD) is the leading cause of death in patients with SSc. Myofibroblasts are the final mediators of disease, producing excessive extracellular matrix and distorting the normal architecture. We have previously applied a new technology referred to as single cell RNA-sequencing to gain a more detailed molecular understanding of the mRNA molecules that define how myofibroblasts develop in SSc-ILD. Recently, we have applied another technology, single cell Assay for Transposase-Accessible Chromatin, that enables us to understand the structure of the DNA (epigenome) in myofibroblasts. Together these studies have helped us identify a series of regulators, known as transcription factors and cytokines, that are predicted to control the development of myofibroblasts from progenitor cells. We propose to more definitively characterize the role(s) of these transcription factors and cytokines in controlling myofibroblasts in SSc-ILD by examining the effect of decreasing or increasing the levels of each transcription factor in myofibroblasts, or by treating myofibroblasts with cytokines in cell culture in vitro. We will compare the effect of these perturbations on mRNA molecules and the epigenome of myofibroblasts seen in vivo in SSc-ILD. These studies should open-up new directions for discovery of drugs to block SSc-ILD myofibroblasts.
Elena Netchiporouk, MD, MSc, FRCPC
Investigating the Impact of the Environment on Systemic Sclerosis in Canada The Research Institute of the McGill University Health Centre
Established Investigator Award
In autoimmune disease, a person’s immune system mistakenly attacks healthy tissue and in the past 30 years, the incidence has increased significantly. Interestingly the frequency varies greatly by the geographic location, which suggests that environmental influences and exposures could act as triggers in genetically susceptible individuals. For example, air pollution and silica exposure have been proposed to play a role in the development of systemic sclerosis (SSc), a severe progressive scarring disease that involves the skin and many internal organs. The goal of our study is to determine environmental factors which are associated with SSc development to help counsel patients and advocate for medical resource distribution based on areas with high disease burden. To achieve this, we will obtain data on all SSc cases from the provincial healthcare records and map them using the Forward Sortation Area (first 3 digits of a postal code) to determine if there is uneven geographic distribution. Then, air pollution levels, industry density, and neighborhood characteristics will be compared between areas with high levels of disease to those with low levels to identify possible environmental factors associated with SSc development. From a public health perspective, this will help researchers and decision-makers to elaborate preventative strategies.
Peter Morawski, PhD
Cutaneous T Cell Dependent Regulation of Scleroderma-associated Fibroblasts Benaroya Research Institute at Virginia Mason
New Investigator Award
Systemic sclerosis is a fibrotic disease of the skin and underlying tissues. It has the highest mortality of any rheumatologic illness, the cause of disease is unknown, available treatment options for patients are limited, and there is no known cure. Dysfunction of the immune system, especially white blood cells known as T cells, is believed to be a major driver of scleroderma, but the details of how these cells promote disease remain unclear. Understanding how T cells can influence other skin cells like structural fibroblasts, could identify novel pathways to target for future therapeutics. We hypothesize that T cell-fibroblast crosstalk is central to scleroderma pathology. This proposal will utilize innovative single-cell imaging techniques, novel three-dimensional engineered skin cultures, and advanced reverse genetics techniques to fill critical knowledge gaps about T cells during disease and overcome existing technical hurdles in the field to inform future therapeutics for scleroderma. The team assembled for this work is highly skilled in studying immune-mediated disorders and the work is being performed at a world-renowned institute for the study of human immunology. Therefore, this project has the highest potential to further our understanding the impact of immune cell function on fibrotic skin disease.
Andreea Bujor, MD, PhD
Spatial Frequency Domain Imaging as a New Method to Quantify Skin Changes in Scleroderma Boston University
Established Investigator Award
This project will use a new kind of device, called spatial frequency domain imaging (SFDI), to quantify skin changes in scleroderma. SFDI projects light onto the skin surface, and provides a quantitative value related to the amount of light scattering that occurs in the skin (“scattering coefficient”). To do this, SFDI will be applied to patients and results will be compared with the current “gold standard” (skin pitching also called the modified Rodnan skin score or mRSS). Additionally, SFDI results will be correlated with other measures of skin involvement in scleroderma, including patient reported outcomes, ultrasound and biopsy. Our preliminary data indicates that SFDI has a strong correlation with the mRSS and can differentiate between healthy individuals and patients with scleroderma that have no obvious skin fibrosis by gold standard. Using this device is easy, fast, noninvasive and gives objective results. This may help clinicians to detect fibrosis in the skin at an earlier stage, and more accurately assess the response to a specific therapy. Since early intervention can improve survival in this disease, our proposed work would potentially help scleroderma patients live better and longer lives.
Suzanne Li, MD, PhD
Developing Classification Criteria for Juvenile Systemic Sclerosis: An International Effort to Enable Pediatric-focused Clinical Trials Hackensack University Medical Center
Established Investigator Award
This study proposes to develop juvenile systemic sclerosis (jSSc) classification criteria, an essential tool for conducting trials. Unlike adult SSc, no jSSc clinical trials have been done, so there is little data to guide care. The many differences between pediatric and adult onset disease strongly suggest jSSc-specific treatment strategies are needed. Differences include organ involvement patterns, longer disease duration in jSSc, and risk for impaired growth in jSSc. Our initial findings suggest we can develop high performing jSSc criteria from the 2013 adult classification criteria. This study will be led by a steering committee that has jSSc, adult SSc, and methodological expertise. We will follow established guidelines for developing criteria including generating two patient cohorts, each containing 200 jSSc cases and 200 non-jSSc mimicker controls. The first cohort will be used to develop and test different jSSc criteria models, and the second to verify that the criteria model performs as expected in an independent sample. We have assembled an international team based on 6 continents to conduct this work to ensure that the cohorts reflect the worldwide jSSc spectrum. This will allow us to generate criteria that are universally applicable, enabling future international jSSc trials and other studies.
The Marta Marx Fund for the Eradication of Scleroderma The Role of Lymphatic ERG Deficiency on Pulmonary Fibrosis
Boston University
New Investigator Award
Lung fibrosis is the leading cause of mortality amongst systemic sclerosis (SSc) patients. Vascular dysfunction contributes to the progression of SSc pulmonary fibrosis. Although not yet demonstrated in SSc, lymphatic dysfunction could also trigger pulmonary fibrosis. We observed lymphatic rarefaction in human SSc lungs. Here, we aim to investigate potential link between pulmonary lymphatic defects and SSc fibrosis. We target ERG (ETS related) gene expression, shown to be involved with blood vasculature defects in SSc. Based on our preliminary data, we hypothesize that ERG is also critical for lymphatic function. The functional consequences of lymphatic endothelial cells (LECs) ERG loss will be investigated for the first-time using ERG deficient mice. The molecular characteristics of pulmonary LECs will be examined upon ERG deletion. My long term-goal is to better understand the role of defective lymphatic system in SSs lung fibrosis, which may help in to improve future treatment options for SSc patients.
Janet L. Poole, PhD, OTR/L
Mark Flapan Award Feasibility and acceptability of the Making it Work Program for Systemic Sclerosis
University of New Mexico Health Sciences Center
Established Investigator Award
The purpose of this study is to develop and test an online program to help people with systemic sclerosis remain employed and lead healthy and productive lives at work. Based on an existing program in Canada [Making it WorkTM Inflammatory Arthritis (MiW-IA)], this program involves completing 5 online modules, 5 virtual group sessions every 2 weeks, and a 1-1 virtual meeting with an occupational therapist and vocational counselor. To make sure the program addresses the needs of persons working with systemic sclerosis in the United States, we will first gather input from patients working with systemic sclerosis and rheumatology and employment experts and make necessary changes to the program’s content and format. Second, we will recruit patients working with systemic sclerosis to go through the program, gather more feedback about the program, and examine if the completion of the 12-week program [now Making it Work-Systemic Sclerosis (MiW-SSc)] leads to improvements in job self-efficacy and work productivity, and decreases the amount of sick leave taken and risks for needing to stop employment. At the end of the project, we will have a virtual educational program that empowers persons with SSc to problem solve workplace challenges and remain in the workforce.
Patrizia Fuschiotti, PhD
Walter & Marie Coyle Research Grant Molecular Mechanisms of CXCL13+ T Cell-B Cell Interactions in Inflammatory Systemic Sclerosis Skin Lesions
University of Pittsburgh
Established Investigator Award
Scleroderma is a chronic disease that causes skin and sometimes internal organs to become hard and tight (fibrosis). This occurs when the body makes too much collagen, the protein that supports the skin and visceral organs. Scleroderma is considered an autoimmune disease, meaning that the immune system mistakenly attacks the body’s own tissues. Activation of the immune system induces inflammation and accumulation of white blood cells in the skin and other involved organs. These cells are thought to secrete proteins called cytokines and chemokines that induce a persistent chronic inflammation, which is accompanied by overproduction and accumulation of factors and cells involved in tissue damage and fibrosis in the skin. We have recently found that CXCL13, a pro-inflammatory chemokine is highly expressed in the skin of scleroderma patients, particularly in the early stages of the most severe forms of cutaneous fibrosis. We have identified a specific group of white blood cells in the skin of patients that produce CXCL13 and we propose to study their role in inducing chronic inflammation in scleroderma skin and ways to inhibit it. There is currently no therapy that can reverse or even slow the natural progression of scleroderma. We expect that our proposal will lead to the development of new therapeutic strategies for this incurable disease.
Robert Lafyatis, MD
Debra Lurvey Memorial Research Grant Award Cooperative Transcription Factor Regulation of Myofibroblast Differentiation in Scleroderma-Associated Interstitial Lung Disease
University of Pittsburgh
Established Investigator Award
Systemic sclerosis (SSc) associated interstitial lung disease (ILD) is the leading cause of death in patients with SSc. Myofibroblasts are the final mediators of disease, producing excessive extracellular matrix and distorting the normal architecture. We have previously applied a new technology referred to as single cell RNA-sequencing to gain a more detailed molecular understanding of the mRNA molecules that define how myofibroblasts develop in SSc-ILD. Recently, we have applied another technology, single cell Assay for Transposase-Accessible Chromatin, that enables us to understand the structure of the DNA (epigenome) in myofibroblasts. Together these studies have helped us identify a series of regulators, known as transcription factors and cytokines, that are predicted to control the development of myofibroblasts from progenitor cells. We propose to more definitively characterize the role(s) of these transcription factors and cytokines in controlling myofibroblasts in SSc-ILD by examining the effect of decreasing or increasing the levels of each transcription factor in myofibroblasts, or by treating myofibroblasts with cytokines in cell culture in vitro. We will compare the effect of these perturbations on mRNA molecules and the epigenome of myofibroblasts seen in vivo in SSc-ILD. These studies should open-up new directions for discovery of drugs to block SSc-ILD myofibroblasts.
Monica Mukherjee, MD, MPH
Echocardiographic Risk Prediction of Mildly Elevated Pulmonary Pressures in Systemic Sclerosis
Johns Hopkins University
Established Investigator Award
Pulmonary arterial hypertension (PAH) commonly complicates patients with the autoimmune disease systemic sclerosis (SSc) and is a leading cause of death in this population due to right ventricular (RV) failure. In an effort to identify PAH earlier in the disease and prevent associated morbidity and mortality, the definition has recently changed to incorporate SSc patients with mildly elevated pulmonary pressures (SSc-MEP). However, how the updated definition impacts current screening methods remains unclear. We recently demonstrated the utility of innovative echocardiographic techniques to detect abnormalities in RV contractility in SSc patients. In the current proposal, we will apply these techniques to determine which (1) echocardiographic parameter or combination of parameters best identifies SSc-MEP patients and can therefore be used to predict adverse clinical outcomes, and (2) to establish the relationship between these echocardiographic measures and direct hemodynamic measures of contractility at the chamber and cardiomyocyte levels in SSc-MEP patients. We are uniquely positioned to study these critical questions given our access to one of the largest and finely phenotyped SSc cohorts in the world, our strong track record of excellence in the assessment of RV function in SSc, and our expertise in the complex statistical methodology necessary to complete this project.
Kerri Ilene Aronson, MD, MS
Development of a Stakeholder Engaged Intervention to Improve Knowledge and Health-Related Quality of Life in SSc-ILD
Weill Medical College of Cornell University
New Investigator Award
Interstitial lung disease (ILD) is a common and devastating diagnosis for patients living with Scleroderma. People living with Scleroderma-related ILD (SSc-ILD) experience negative impacts on their quality of life as a result of symptoms and psychosocial consequences of living with the disease.There is significant uncertainty and lack knowledge about SSc-ILD amongst patients. In our prior research, we found that uncertainty and lack of knowledge about ILD precipitates anxiety, fear, and frustration further impacting quality of life. Unfortunately, there are few interventions available to address disease-specific knowledge and quality of life in SSc-ILD.
There remains a large deficit of accurate and patient-friendly education material that addresses SSc-ILD. Additionally, we have not yet identified the exact questions that cause the most uncertainty, anxiety, fear, and frustration amongst patients living with SSc-ILD. We plan to develop a curriculum about SSc-ILD using the Patient Activated Learning System (PALs), a digital interactive evidence-based patient education platform. The intervention will be developed using input from patient and physician stakeholders. We then plan to study how the PALs intervention impacts patients’ disease-related knowledge, self-efficacy, and quality of life. This proposal aligns with the mission of the National Scleroderma Foundation to provide patient support through education and research.
Peter James Niedbalski, PhD
MRI for Screening and Monitoring Systemic Sclerosis Interstitial Lung Disease
University of Kansas Medical Center Research Institute
New Investigator Award
Interstitial lung disease (ILD) is a common and serious complication of scleroderma that leads to ~35% of scleroderma related deaths. It can be challenging both to diagnose and to monitor scleroderma-associated ILD (SSc-ILD). The gold standard for SSc-ILD diagnosis is computed tomography (CT) imaging, but this type of imaging delivers ionizing radiation and thus is not ideal for repeated imaging or imaging in young patients.
Other clinical variables, such as lung function tests, are not specific to SSc-ILD and are insensitive to changes in lung function. As such, new techniques for diagnosing and monitoring SSc-ILD are urgently needed. Novel lung MRI methods may be sensitive to the lung damage that occurs in SSc-ILD. Ultra-short echo time MRI provides images of the lungs that have similar quality to CT imaging, and thus may be an ionizing-radiation-free alternative to CT for SSc-ILD diagnosis. Additionally, hyperpolarized 129Xe MRI, in which xenon gas is imaged within the lungs, has proven to be highly sensitive to lung damage caused by ILD. As such, this technique may be effective for monitoring treatments in SSc-ILD. This could facilitate both improved care in the short term and development of new, more effective therapies in the long term.
Sean M. Fortier, MD
Lung and Skin Myofibroblast De-Differentiation and Fibrosis Resolution in Systemic Sclerosis Depend on cAMP-Mediated Inhibition of p38
University of Michigan
New Investigator Award
Systemic sclerosis (SSc) – also known as scleroderma – is a chronic incurable autoimmune disease characterized by tissue injury that leads to scarring (fibrosis) of the skin and internal organs. Fibrosis in SSc leads to organ dysfunction and, when it affects the lungs, respiratory failure and death. Fibrosis occurs when scar-forming cells called myofibroblasts persist following tissue injury. Although no current therapies reverse fibrosis, it is thought that if myofibroblasts can be deactivated and removed, fibrosis will resolve. It has been shown that fibrotic lungs and skin can undergo spontaneous resolution in mice, but the mechanism is unknown. We hypothesize that cyclic AMP (cAMP) signaling in myofibroblasts is crucial for this resolution and that disruption of this signaling pathway may result in fibrosis. My work has demonstrated that cAMP enhancement can reprogram and deactivate lung myofibroblasts and new preliminary data suggest that it does so through inhibition of the protein p38. We propose to test the effect of cAMP activation and p38 inactivation on myofibroblast deactivation and clearance and determine the role of these two molecules in fibrosis resolution in mice. Answers to these questions will help us better understand how to develop effective therapies for SSc.
Karin Wuertz-Kozak, MS PhD MBA
A Novel 3D Scleroderma Skin Model to Test Therapeutic TRPC6 Modulation
Rochester Institute of Technology
Established Investigator Award
Scleroderma is a rare disease commonly characterized by chronic hardening (fibrosis) of body tissues including the skin due to excessive accumulation of collagen. Despite intensive research, no therapies are effective in treating scleroderma-related skin disease. To test the value of new treatments, human three-dimensional (3D) skin models offer significant advantages over animal models. However, existing 3D skin models are limited in value due to their inability to assess the production of collagen, a critical component of scleroderma. Thus, there is an urgent need for the development of more efficient and reproducible human 3D skin models as a means for the screening of novel scleroderma treatments.
Therefore, the main goal of the first project part is to develop, characterize, and validate a novel 3D human fibrotic skin model (scleroderma model) that allows determining the overproduction of collagen and its normalization following exposure to treatment. We will use a cutting-edge technology called electrospinning to create tissue analogs with high similarity to scleroderma skin.
Our preliminary results show that activation of TRPC6 (an ion channel present in the skin) leads to increased collagen synthesis and crosslinking, which in turn can be prevented by pharmacological
inhibitors of TRPC6.
This highlights that TRPC6 constitutes a promising anti-fibrotic drug target for the targeted treatment of scleroderma-related skin problems.
The main goal of the second project part is to investigate the potential of TRPC6 as a therapeutic target of scleroderma. Experiments will first be conducted in classical 2D culture and thereafter in the new 3D human fibrosis model. We will also utilize these experiments to verify the potential of using the new electrospun 3D fibrotic skin model to reduce costs, improve scientific rigor, and speed up the discovery of scleroderma therapeutics.
We believe that the project will help scleroderma patients that suffer from hardening and tightening of the skin and associated problems, such as limited range of motion of the hands and extremities, tightness of the face, and change in body habitus. The development of a novel, fibrotic 3D skin model for scleroderma in the first part of the project will promote the development of new therapeutic approaches (Innovation 1). The second part of the project will directly investigate a new therapeutic approach with high potential, and will hopefully result in the first effective treatment for scleroderma patients suffering from skin hardening and tightening (Innovation 2).
Although further experiments on safety and efficacy will be needed following a positive study outcome, this research will lay the groundwork to better understand the molecular mechanisms underlying the development and progression of scleroderma, and to realize improvements in the care and quality of life of those affected by scleroderma-induced skin alterations.
Deepa Soundara Rajan, MD
“Are Somatic Mutations Underlying Craniofacial Scleroderma Phenotypes?”
University of Pittsburgh
New Investigator Award
Linear scleroderma (LS) of the face and scalp is a scarring autoimmune connective tissue disease and is one of the most debilitating subtypes. It is disfiguring and disabling, especially if the disease begins during childhood, causing prominent skull ridges, dental issues, distorted facial features and neurological problems including seizures and stroke. While inflammation occurs in active LS skin lesions followed by fibrosis, the underlying molecular mechanisms are not well defined. Identifying genes involved in inflammation and fibrosis may help us understand why LS occurs and help develop more effective therapies. Our pediatric craniofacial scleroderma clinic is one of the only comprehensive clinics nationally and we are well equipped to investigate these genes due to the expertise of the investigators and access to the largest scleroderma database and specimen bank: the National Registry of Childhood Onset Scleroderma (NRCOS, Pitt). This study utilizes innovative whole genome sequencing that will identify somatic genetic mutations, distinctive in affected tissue compared to unaffected tissue and novel single cell RNA technology to understand the immunological signature in affected tissue. Findings from the study will provide insight into how LS develops and support development of more effective and targeted therapies, leading to improved outcomes.
Yue Ding, MD
The Development of TRPM8 Targeted Therapy Against Raynaud’s Phenomenon
University of Toledo
New Investigator Award
Raynaud’s phenomenon (RP) is a condition that affects up to 10% of the general population and is seen in many patients with connective tissue disorders. In scleroderma (systemic sclerosis, SSc), RP is observed in more than 97% of patients. Current therapeutic strategies against RP have limited effectiveness and are often associated with detrimental side effects. The reasons behind enhanced cold sensitivity in RP patients are still unclear. Our preliminary data along with other literature in the field convincingly indicate that a cold sensing cation transporter protein, TRPM8 (transient receptor potential Melastatin 8), is overexpressed in skin cells of SSc patients. TRPM8 activation leads to enhanced blood vessel spasm and decreased ability of the vessel to dilate, thus the findings support a role for TRPM8’s in mediating attacks of RP. We found that inhibiting TRPM8 with the drug capsazepine normalizes the blood vessel spasm/dilation homeostasis when cells are exposed to the cold.
This study aims to test our preliminary findings in humans and develop an optimized formulation of a TRPM8 inhibitor that can be topically applied in RP patients. We will measure the permeability of the most optimized topical formulation to attain maximum therapeutic bioavailability and further test the efficacy of these stable and potent TRPM8 inhibitors on the digits to prevent RP. Finally, as a first proof of concept human study, we will perform clinical efficacy of the TRPM8 inhibitors in RP patients. We envision that this study will allow us to ascertain the mechanism and TRPM8 role in cold sensing in RP. Also, this study will translate the utility of the most optimized topical formulation of a TRPM8 inhibitor in the treatment of RP.
DeAnna A. Baker Frost, MD, PhD
The Role of Estradiol Production in Systemic Sclerosis
Medical University of South Carolina
New Investigator Award
Although patients who develop scleroderma have increased disability and death, there are no FDA-approved medications to treat the skin disease. Our previous research showed that some patients with scleroderma produce more estrogen than those without scleroderma. Also, human skin tissue and cells treated with estrogen can increase proteins that lead to fibrosis. Our long-term research goal is to understand how estrogen leads to fibrosis and if blocking estrogen production is a potential treatment for scleroderma. The objective of is to identify the steps that occur due to estrogen production in human skin cells, tissue, and mice to cause fibrosis. Our theory is when estrogen is produced, it activates the cells to make fibrotic proteins. We will test our theory through studying estrogen production in mice and blocking estrogen production in human skin cells from scleroderma patients. We will then look for a change in the proteins and genes linked to fibrosis. Additionally, we will measure genes in mice to look for unexpected genes that impact fibrosis. The research is innovative because it focuses on understanding estrogen’s role in scleroderma. This information is important because it may lead to the development of new medications that block estrogen as a treatment for scleroderma.
The Marta Marx Fund for the Eradication of Scleroderma Comprehensive Single Cell Analysis of Skin and Blood of Scleroderma Patients: Towards Identification of Disease Molecular Mechanisms, Prognostic Biomarkers and Potential Therapeutic Targets.
Weizmann Institute of Science
Established Investigator, Two‑Year Award
Jonathan A. Garlick, DDS, PhD
Mark Flapan Award Functional Analysis of Cellular Diversity and Cell-Cell Interactions in Scleroderma 3D Skin-Like Tissues
Tufts University School of Dental Medicine
Established Investigator, Two‑Year Award
Hans Dooms, PhD
Walter & Marie Coyle Research Grant Functional Characterization of Aberrant PD-1+TIGIT+T Cell Subsets Expanded in Systemic Sclerosis Patients
Boston University
Established Investigator, Two‑Year Award
Harry Karmouty-Quintana, PhD
The Role of SIX1 in SSc-ILD
University of Texas Health Science Center at Houston
Established Investigator, Two‑Year Award
Mengqi Huang, PhD
Investigation of Disease Associated Skin Endothelial Cells in Systemic Sclerosis Using Single-Cell Transcriptomics and Epigenomes
University of Pittsburgh
New Investigator, Three‑Year Award
Kimberly Showalter, MD, MS
Dermal Fibroblast Immunophenotype to Predict Clinical Trajectory in Early and Late Diffuse Systemic Sclerosis
Hospital for Special Surgery
New Investigator, Three‑Year Award
Stephanie Stanford, PhD
LCM-RNAseq for Topological Mapping of Scleroderma Skin Pathology
University of California, San Diego
New Investigator, Three‑Year Award
Yan Wang, MD, PhD
The Role of Hyaluronan and O-GlcNAcylation in Fibroblast Turnover and Function in Scleroderma
Cleveland Clinic Foundation
New Investigator, Three‑Year Award
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