Letter from Madeline C. McNamara, United States Department of State, to Geraldine Ferraro

Letter from Madeline C. McNamara to Geraldine Ferraro, on behalf on the Italian Desk at the Office of Western European Affairs of the United States Department of State. Letter has handwritten notes.https://ir.lawnet.fordham.edu/vice_presidential_campaign_correspondence_1984_international/1366/thumbnail.jp

An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death.

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-β inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.This work was supported by Evelyn Trust, the NIHR Cambridge Biomedical Research Centre and the British Heart Foundation (FS/13/29/30024, RM/l3/3/30159, FS/11/77/29327).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ng.372

The Lantern, 2011-2012

• Frangipani • A Shadow • Dear Anne, In this Place, Stringbean Girls • Back to a Dandelion • How to Plant a Room • Swimming Pool Poem 30 • The Naming of Daughters • Berman Museum Photographs • Truth or Dare • The Song of Remembrance, L\u27vov, Poland, 1940 • Headlights • Prayer of Thanks • Numbers Game • Pediment • Home Sick • Lust • Sand Lining Instructions • A-A-Ask a Question • Flash Cards • Columbus Day • Mr. Yoest Gives His Report to the Police Officers on Wednesday Night • Gender Trouble • The Internet Connection at Ursinus College • Assuming You\u27ll Still be Here • 10/28/11, Third Poem • October • Actions that Affirm and Confirm Us as a Community • Why I Hate The Lantern • Confessions of an Ex-Vegetarian • Run • Lunch at Caltort • Schemers • You Will Make Beautiful Babies in America • The Black Dirt Region • Il Travatore • Ghost Story • Blue Eyes and Sunny Skies • A Little Sincerity • The Bookstore • The Opposite of Serendipity • The Human Doll • Evil Deeds • Francesca • Sunday Morning • Jersey Aesthetic • Jump! • Behind Reimert • Seaweed in New Zealand • Tombee de L\u27elegance • The Window • Esperando • Rainbow to the Heavens • Encased • In Springtime • A Fiesolan Monk\u27s Room • Inside a Bone • Neon Indian • Moments of Clarity • OneFeral: A Feral Self-Portrait • Cover Image: The Conquerorhttps://digitalcommons.ursinus.edu/lantern/1177/thumbnail.jp

Development of Novel Therapies for Marfan Syndrome using a Human iPSC-disease model

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1, a matrix component encoded by the gene FBN1, with pleiotropic manifestations including severe cardiovascular complications, such as aortic aneurysms and dissection. Current treatments focus on surgically removing the aneurysm or on minimising aortic wall stress by controlling haemodynamics, but neither of these strategies tackle the underlying pathology. Although MFS is caused by fibrillin-1 mutations, it remains unclear how these lead to the pleiotropic manifestations seen in patients. Defective fibrillin-1 is thought to lead to excessive release of TGF-β in the extracellular environment, which will increase TGF-β signalling activity. Substantial efforts observed that angiotensin II receptor (AngIIR) blockade is able to rescue promiscuous TGF-β signalling and aortic complications in a MFS mouse model (Habashi et al. 2006). However, results in clinical trials have been disappointing (Lacro et al. 2014) and it is increasingly apparent that there is a need to develop better disease models for MFS to improve therapy development. In addition to abnormal TGF-β signalling, matrix degradation is a likely crucial component for pathology development as most clinical studies show extracellular matrix degradation and increased matrix proteolytic enzyme levels in diseased aortas (Chung et al. 2007; Xiong et al. 2012). In this work, I speculate that there are multiple disease perturbations downstream of the FBN1 mutations and that there is a need to develop novel strategies to identify new putative disease mediators and signalling pathways that participate in the pathogenicity. Here, I use a patient iPSC-derived in vitro disease model that recapitulates the complexity of the patient abnormalities (Granata et al. 2017) to develop two potential therapeutic strategies (i) directly interfering at the level of the pathological mutation using an exon skipping approach and (ii) designing an unbiased phenotypic drug screen to identify putative compounds able to rescue abnormal proteolysis in our disease model. These complementary techniques will enable the identification of novel disease-causing pathways and offer strategies for clinical intervention using our in vitro disease model as a platform for drug discovery.BHF Regenerative Medicin

Letter from Madeline C. McNamara, United States Department of State, to Geraldine Ferraro

Letter from Madeline C. McNamara to Geraldine Ferraro, on behalf on the Italian Desk at the Office of Western European Affairs of the United States Department of State. Letter has handwritten notes.https://ir.lawnet.fordham.edu/vice_presidential_campaign_correspondence_1984_international/1366/thumbnail.jp

The experience of living with Type 1 Diabetes and attending clinic from the perception of children, adolescents and carers: Analysis of qualitative data from the DEPICTED study

Type 1 diabetes (T1D) is a complex, invasive childhood condition. Optimal glycemic control, essential to minimize risk of life-changing complications, is difficult to achieve. The DEPICTED trial evaluated a training program in consultation skills for pediatric diabetes teams. Qualitative descriptive analysis of questionnaire free-text comments from children, adolescents and carers participating in DEPICTED identified the emotional impact of living with T1D and how health professionals' communication skills in clinic influence the patient/carer experience. Healthcare professionals caring for children/adolescents with T1D and carers need training in patient-centered communication skills. Emotional needs of patients/carers need to be systematically assessed and addressed

A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target.

Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutations in FBN1. Patients with MFS notably suffer from aortic aneurysm and dissection. Despite considerable effort, animal models have proven to be poorly predictive for therapeutic intervention in human aortic disease. Patient-derived induced pluripotent stem cells can be differentiated into vascular smooth muscle cells (VSMCs) and recapitulate major features of MFS. We have screened 1,022 small molecules in our in vitro model, exploiting the highly proteolytic nature of MFS VSMCs, and identified 36 effective compounds. Further analysis identified GSK3β as a recurring target in the compound screen. GSK3β inhibition/knockdown did not ameliorate the proliferation defect in MFS-VSMCs but improved MFS-VSMC proteolysis and apoptosis and partially rescued fibrillin-1 deposition. To conclude, we have identified GSK3β as a novel target for MFS, forming the foundation for future work in MFS and other aortic diseases