Our Grant Awardees - National Scleroderma Foundation

The National Scleroderma Foundation has proudly awarded more than $30 million in scleroderma research grants since 1989, including awards made by its predecessor organizations, the United Scleroderma Foundation and the Scleroderma Federation. 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.

2022 Grant Awardees

Adri Chakraborty, PhD

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.

2021 Grant Awardees

Ido Amit, PhD

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