Research Project Highlights

U-M Division of Rheumatology, Dr. Eliza Tsou

Eliza Tsou, PhD

Project: Identification of Cysteine-Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma
Sponsor: Scleroderma Foundation and Arthritis National Research Foundation
Role: Principal Investigator

Eliza Tsou, PhD; Dinesh Khanna, MD, MSc; and Amr Sawalha, MD recently published their work “Identification of Cysteine-Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma” in Arthritis & Rheumatology (A&R). It is a follow-up study from a previous publication in A&R.

Using next-generation techniques to scan the genes in endothelial cells isolated from skin biopsies from scleroderma patients, Dr. Tsou discovered CYR61, a histone deacetylase 5-controlled gene that is critical for the function of these cells (Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors). Since this gene also affects fibrosis, another key feature of scleroderma, they hypothesize that CYR61 is beneficial for scleroderma through its anti-fibrotic and pro-angiogenic properties. This makes CYR61 a great candidate for drug development.

In the recent publication, Dr. Tsou showed the molecular mechanisms involved in the effect of CYR61 in scleroderma endothelial cells. She also demonstrated the anti-fibrotic potential of this protein in scleroderma dermal fibroblasts. She showed that overexpressing CYR61 converted scleroderma fibroblasts from extracellular matrix (ECM)-producing myofibroblasts into ECM-degrading senescent cells. Based on these observations, it is clear that CYR61 acts as a pro-angiogenic and anti-fibrotic in this disease.

In addition to angiogenesis and fibrosis, CYR61 has been described to influence immune responses by affecting immune cell migration and inflammation. It also activates a pro-inflammatory genetic program in macrophages characteristic of the classically activated M1 phenotype. Dr. Tsou is currently expanding her work on CYR61 to examine whether CYR61 affects macrophages in scleroderma.

U-M Division of Rheumatology, Dr. Jason Knight

Jason Knight, MD, PhD

Project: Role of Neutrophil Extracellular Traps in Diabetic Cardiovascular Disease
Sponsor: Michigan Diabetes Research Center (MDRC)
Role: Principal Investigator
The goal of this project is to determine the extent to which NETosis is a driver of vascular dysfunction in a mouse model of type 1 diabetes. The Knight lab has previously shown that hyperactive neutrophils are important drivers of cardiovascular disease in inflammatory conditions such as lupus and antiphospholipid syndrome. The Michigan Diabetes Research Center is supporting preclinical studies in the Knight lab to determine the extent to which similar pathophysiology may be at play in diabetics. The long-term goal of this work is to establish novel approaches for the treatment of diabetic cardiovascular disease, a leading killer of Americans.
Project: Defibrotide as a Regulator of Neutrophil Extracellular Traps (NETs) and Endothelial Cells in Antiphospholipid Syndrome
Sponsor: Jazz Pharmaceuticals
Role: Principal Investigator

The major goal of this project is to determine the extent to which defibrotide prevents NET release, especially in response to thromboinflammatory stimuli such as antiphospholipid antibodies and activated platelets. We will also test whether defibrotide mitigates adhesion of neutrophils to the endothelium, and consequently endothelial damage, in antiphospholipid syndrome.
The catastrophic variant of antiphospholipid syndrome (CAPS) remains one of the deadliest conditions in all of rheumatology. Jazz Pharmaceuticals is supporting preclinical studies in the Knight lab to determine the extent to which a unique medication called defibrotide (currently approved for the treatment of hepatic veno-occlusive disease in transplant patients) may neutralize the thromboinflammatory state of antiphospholipid syndrome. The long-term goal of this work is to eventually offer a treatment for CAPS that is more effective at preserving organs and lives.

U-M Division of Rheumatology, Dr. Vivek Nagaraja

Vivek Nagaraja, MBBS

Project: Integration of Patient-Reported Outcome Measurement into Clinical Rheumatology Practice
Sponsor: Blue Cross Blue Shield of Michigan Foundation Physician Investigator Research Award
Role: Principal Investigator

Rheumatic diseases have a detrimental effect on self-reported physical, mental, and social health, i.e., health-related quality of life (HRQoL). Patient-reported outcome measurements (PROMs) reflect the impairment in HRQoL domains in patients with RDs and can enhance clinical decision making. The objectives of this project are to integrate PROMs in clinical rheumatology practice at Michigan Medicine and enhance rheumatology health-care provider engagement in the use of PROMs in the chronic care of patients with rheumatic diseases.

Project: The ArthritisPoer Trial - A Multi-Center Cluster Randomized Controlled Clinical Trial to Determine the Impact of a Mobile Health Application on Rheumatoid Arthritis Shared Decision Making
Sponsor: Pfizer Global Healthy Living Foundation Independent Grants for Learning & Change - Rheumatoid Arthritis Shared Decision Making
Role: Co-investigator in collaboration with Mayo Clinic and Ohio State University

The fundamental concept of this project is that collecting patient-provided information on disease activity and health status between clinic appointments and providing this information to patients and their rheumatology health care providers (HCPs) at the time of face-to-face clinical evaluation will improve the quality of patient-HCP interaction and communication, resulting in enhanced agreement on shared decisions that lead to greater attainment of disease activity targets and improvement of HRQOL. We proposed to use the ArthritisPower™ app every week as the intervention.

U-M Division of Rheumatology, Dr. Eliza Tsou

Pei-Suen (Eliza) Tsou, PhD

Project: BET Bromodomain Proteins in Scleroderma Fibrosis
Sponsor: American Autoimmune Related Diseases Association (AARDA) Young Investigator Award
Role: Principal Investigator
Scleroderma is characterized by inflammation, scarring of the skin, and decrease in blood vessel formation throughout the body, all of which trigger potentially lethal damage to the organs. In our lab, we are interested in studying epigenetics, which is the study of changes in gene activity that are not caused by changes in the DNA sequence. We plan to examine a class of epigenetic proteins that “reads” the epigenetic marks on DNA, thereby controls which genes are turned “on” or “off”. It has been suggested that these histone “readers” BET bromodomain proteins (BRDs) promote tissue scarring in various organs and animal models. However, their role in scleroderma has not been examined.
We intend to inhibit BRDs in dermal fibroblasts derived from scleroderma patients as well as an animal model of scleroderma, and examine whether blocking BRDs improves the disease. We also will use an integrated approach including next-generation sequencing, epigenomics, and bioinformatics to identify novel genes that are critical for causing tissue scarring in scleroderma.  
Our goal is to generate sufficient evidence to explore the possibility of using BRD inhibitors as a therapeutic option for this disease.

U-M Division of Rheumatology, Dr. Beth Wallace

Beth Wallace, MD

Project: Rheumatologist Proclivity to Prescribe Glucocorticoids for Rheumatoid Arthritis Management
Sponsor: American Autoimmune Related Diseases Association (AARDA) Young Investigator Award
Role: Principal Investigator
There are no guidelines to help doctors adjust the way they use steroids in response to patients’ risk factors. For this reason, different doctors prescribe steroids for RA very differently, even when their patients have the same risk factors. This means a patient might receive more steroids, and therefore have more steroid side effects, entirely because of the doctor they see, and not because of anything having to do with their RA or overall health.
We aim to create a score that tells us how frequently rheumatologists prescribe steroids to their RA patients. We will then find out what things about rheumatologists and their RA patients most affect this score, and see if we can use the score to predict how much steroids a certain rheumatologist’s patients actually get. This will help us determine why doctors practice the way they do, and what tools might work best to help reduce unnecessary steroid use.