Recent News

The IMRF is pleased to announce that it has funded a project to develop a mouse model for neonatal Marfan syndrome under the direction of Dr. Dirk Hubmacher. Neonatal Marfan syndrome is the most severe form of Marfan syndrome, a connective tissue disorder that affects 1-2 in 5,000 newborns. Most individuals diagnosed with neonatal Marfan syndrome die within their first two years of life due to heart failure caused by an abnormally extended aorta, which is the largest blood vessel in the body, and abnormal heart valves. Dr. Hubmacher’s team will delete a small part of the fibrillin-1 gene in mice to mimic the genetic alteration in the fibrillin-1 gene that was identified in two individuals diagnosed with neonatal Marfan syndrome. The fibrillin-1 gene encodes a protein that is secreted by many cell types and is deposited in connective tissues of blood vessels, the lung, bones, skeletal muscle, and the eye. Once outside of the cell, the fibrillin-1 protein forms cable-like structures that can serve as a scaffold for other components of connective tissues and that can regulate cell behavior and mechanical tissue properties. Ultimately, the goal of the project is to understand why some mutations in the fibrillin-1 gene cause neonatal Marfan syndrome and what makes them different from fibrillin-1 mutations that cause classical MFS. This information can then be harnessed to delineate and test possible treatment strategies for neonatal Marfan syndrome. 

The IMRF is excited to announce it has funded a research proposal studying issues related to preterm birth under the direction of Dr. Sandra Resnik at St. John’s University. Preterm birth affects 15 million babies a year and is the leading cause of mortality and illnesses with lifelong consequences among neonates. The cervix is an organ composed mostly of connective tissue that serves as the gatekeeper for birth. When this protective barrier transforms into a passage to allow the baby to be born, it undergoes profound structural changes known as cervix ripening. While factors that contribute to causes of preterm birth are varied, ripening results from degradation of collagen structure, a consequence of immune cell mediated inflammation. We have discovered that N,N-dimethylacetamide (DMA), a compound currently used as an “inert” ingredient in many drug formulations, has anti-inflammatory properties that include the prevention of preterm birth in a well-established model of inflammation-induced preterm birth. This proposal partners with an expert in the reproductive immunology of prepartum cervix ripening to determine whether the anti-inflammatory actions of DMA prevent preterm birth by forestalling cervix ripening. Studies in Aim 1 will for the first time compare the time course for ripening in mice rescued from preterm birth by treatments with DMA. In Aim 2, studies will investigate the biomolecular mechanism of action whereby DMA blocks cervix ripening and thereby prevents preterm birth. The principal objective of this project is to identify approaches that will lead to the first approved treatment to prevent preterm birth in women.  The ultimate goal is to learn when and how a safe and effective therapy can be provided to prolong pregnancy and ensure the well-being of the newborn in women at risk for preterm birth. 

The IMRF has recently funded a research proposal studying adipose tissue under the direction of Dr. Stanton L. Gerson, Director of the Case Comprehensive Cancer Center and the National Center for Regenerative Medicine at Case Western Reserve University. Adipose tissue is specialized connective tissue that functions as the major storage site for fat in the form of triglycerides. Our hypothesis is that adipose is a key regulator of inflammation and regeneration of connective tissues. Adipose is located throughout connective tissues and both impacts and mitigates all diseases of connective tissue. Maintenance of adipose (fat) cells throughout connective tissues likely mitigates inflammation, provides an energy source for connective tissue repair, and provides proper density and interactions between cell types and buffers tissue layers. Adipocytes are the major cell type residing in the adipose tissue, and they are supported and renewed through signals provided by the extracellular matrix (ECM) throughout connective tissue spaces. Dr. Gerson and his team will be studying the means by which the ECM signals the body to produce mature adipocytes. Previous studies suggest that integrin beta-1 (Itgb 1) plays a role in this process. Work by Dr. Gerson and his team are establishing a link between Itgb 1 and peroxisome proliferator-activated receptor gamma (PPARγ). This transcription factor is involved in inflammation of connective tissues, glucose regulation, and diabetes. The specific nature of the interaction between Itgb 1 and PPARγ will be investigated in the study. Understanding these signaling pathways will uncover new approaches to accelerating regeneration and controlling inflammation of connective tissues.

The IMRF has recently supported Dr. Sophia Liu’s research on idiopathic pulmonary fibrosis at Mount Sinai Hospital in New York.

Idiopathic pulmonary fibrosis (IPF) is a rare and fatal disease which causes progressive scarring in the lungs making breathing difficult. It prevents the lungs from delivering enough oxygen to the bloodstream for usual activity. The National Institute of Health estimates that approximately 100,000 adults in the U.S. have IPF, as well as approximately 3 to 5 million worldwide. Most affected patients survive 3 to 5 years after diagnosis. There is currently no cure for IPF – the current treatment options are limited to delaying disease progression. At present two FDA-approved IPF drugs - Boehringer’s Ofev and Genetech’s Esbriet work on slowing the inexorable decline in lung function but have variable results. Supplemental oxygen and pulmonary rehabilitation help to relieve the symptoms. Some patients may receive a lung transplant, but others are too frail for the procedure. In idiopathic pulmonary fibrosis, fibroblasts are the main effector cells. Once fibroblasts enter the site of injury, they differentiate into contractile and secretory myofibroblasts, which are the principle source for the scarring tissue. The pharmaceutical companies aim to develop anti-fibrotic therapeutic agents that target disrupting and reducing myofibroblast formation. Two main cytokines, transformation growth factor (TGF-β) and Rho-associated coiled-coil forming protein kinases (ROCK) play critical roles in stimulating the fibroblast/myofibroblast differentiation process. Transformation growth factor β is the most potent and well known cytokine inducer involved in IPF. Though TGF-β inhibitors have been in development for decades with newer agents i.e., RNAi which display manageable toxicities. However, the fact that TGF-β inhibition may result in anti-proliferative effects at low concentrations and pro-proliferative effects at higher concentrations, they might not serve as effective inhibitors for IPF. Therefore, it is worth studying whether ROCK inhibitors have anti-fibrotic effects and if so, the possible mechanisms behind it. In this regard, preclinical research studies in animals have showed that integrin plays a role in TGF-β activation, and integrin αvβ6 knockout mice are resistant to develop pulmonary fibrosis. However, clinical data have shown less promising results, Biogen terminated a phase 2 trial of STX-100, the integrin αvβ6 monoclonal antibody in IPF last month due to safety concerns. Moreover, integrin alpha V beta 6 are expressed exclusively on epithelial cells; however, the main effector cells involved in IPF are fibroblasts, which express integrin alpha v beta 1 mainly on the cell membrane. Previous studies have shown a point mutation in the β1 subunit which abrogates binding of integrin α5β1 to fibronectin without disrupting assembly structure. Therefore it would be informative to evaluate whether a point mutation in β1 subunit in integrin αvβ1 can reduce its binding to TGF-β without disrupting its function and expression. It would also provide a tool to study whether ROCK inducing fibroblast/myofibroblast differentiation is TGF-β dependent or not. Recognizing the above, my plan is to use CRISPR technology, which allows gene specific deletion on the binding site in the β1 subunit of αvβ1 integrin to prevent its binding with TGF-β without disruption of β1 subunit expression, to provide more insight to myofibroblast formation.

The IMRF has recently supported Dr. Robert Mecham’s research at the Washington University in St. Louis. Research in the Mecham lab focuses on understanding the biology of microfibrils. These unique matrix structures are found in all tissues from early development through adulthood. Microfibrils band together into large fibers where they have a mechanical role, participate in protein assembly, and regulate growth factor signaling. Their abundance and ubiquity in the ECM of both developing and mature tissues point to an essential role in defining an extracellular environment that influences cellular phenotypes. It is now clear that this “microfibrillar niche” is a significant regulator of tissue development and repair. The vital contributions of the microfibril-associated proteins are just beginning to emerge. Still, it is clear from the broad spectrum of diseases associated with mutation of these proteins that deciphering their functional role is required for understanding the microfibril niche and the molecular basis of human connective tissue disease pathogenesis. The Mecham lab is using advanced light and electron microscopic imaging techniques together with unique animal models to explore microfibril structure and function. Their goal is to understand how microfibrils assemble into functional units and how mutations in microfibrillar proteins lead to disease.

The IMRF is pleased to announce its funding of Dr. James Segars’ research at Johns Hopkins University in Baltimore. Dr. Segars’ research is focused on uterine leiomyomas.

Uterine leiomyomas are benign uterine tumors that occur in 70-80% of US women. The tumors are composed of cells admixed with an abundant fibrous collagen matrix, with the latter feature invoking the common name of “fibroids.” Treatment options for fibroids are limited and many options have deleterious side effects or unwanted consequences. Given the high prevalence of fibroids and the lack of effective non-surgical therapies, it is important that new treatments are developed. Of note, evidence indicates that collagen deposition plays a key role in fibroid growth and development. Collectively, these findings suggest the hypothesis that collagen degradation by the enzyme, collagenase, may represent a promising therapeutic option for fibroid treatment. We are testing this hypothesis by assessing changes in fibroids treated with collagenase compared to untreated controls. In this research study we will measure the stiffness of the injected fibroids, compared to controls, to assess whether collagenase treatment will soften (melt) the fibroids. In additional experiments we will use histochemical stains and electron microscopy to determine whether collagenase treatment leads to changes in the fibrous tissue (matrix) surrounding the cells within the treated area. In the last set of experiments we will measure several markers of cell growth in the collagenase-treated areas to determine whether cells grow, or stop growing, in the treated areas. This research is the necessary first step toward determining whether collagenase may be a helpful treatment for uterine fibroids. If successful, this treatment might ultimately be offered to women with fibroids who do not want a hysterectomy.

The IMRF has recently supported Dr. Mathias Bostrom's research on total knee replacement at the Hospital for Special Surgery in New York. Specifically, Dr. Bostrom is studying how bone mass affects osseointegration.  The grant represents an exciting milestone for the IMRF, as it is the Foundation's first international project. The grant, in conjunction with a stipend from the American Austrian Foundation, will allow an Austrian researcher from Vienna to work in Dr. Bostrom's New York lab. 

The IMRF has teamed up with Drs. Mary K. Cowman and Jin Ryoun Kim of NYU’s Tandon School of Engineering to support their research of serum amyloid A. Serum amyloid A is a protein that has been implicated in connective tissue diseases such as rheumatoid arthritis and psoriatic arthritis. The partnership is especially meaningful to the IMRF as Dr. Mandl was the first female graduate of the Polytechnic Institute of Brooklyn, which merged with NYU in the 2000s. 

The IMRF is pleased to have supported the Campion Fund's workshop, **Uterine Fibroids: A Case for Women’s Health** held in Durham, North Carolina, on March 11, 2017. The workshop was a resounding success by all accounts, featuring a number of presentations by doctors from Johns Hopkins to Duke to North Caroline Central University.

According to the Campion Fund, "The purpose of the meeting was to raise awareness among women of our region regarding uterine fibroids and to the need for increased treatment options. Although, classified as non-malignant tumors, uterine fibroids affect 80% of black women and 70% of white women and are a serious public health problem. The develop around the time of menarche and appear to regress at menopause and grow at different rates. The can develop to various sizes, sometime to a tumor of 20 centimeters, or the size of a five-month pregnancy. They cause pain and serious uterine bleeding and can thus cause severe anemia. In addition, uterine fibroids may interfere with the ability to conceive and they are responsible for pregnancy complications including preterm birth. This debilitating disease has not had the attention it deserves from either the medical or scientific communities. Studies estimate that the costs of this disease to the US pubic and health care system is up to $34.4 billion yearly."

A video of the conference will be posted to this website shortly. For more information, please visit the Campion Fund's website: www.campionfund.org