Scleroderma and Gastrointestinal Disease: Insights into Clinical Phenotypes and Disease Pathogenesis

硬皮病和胃肠道疾病：深入了解临床表型和疾病发病机制

• 批准号: 10374832
• 负责人: Zsuzsanna Hortobagyi McMahan
• 金额: $ 16.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374832
• 关键词: Advisory Committees; Affect; Anatomy; Antibodies; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Responses; Autonomic Dysfunction; Award; Biological; Biological Markers; Biology; Calcium Channel; Cells; Centromere; Cholinergic Receptors; Clinical Management; Collaborations; DNA-Directed RNA Polymerase; Data; Development; Diagnosis; Diagnostic; Disease; Ensure; Enteral; Enteric Nervous System; Enzyme Immunoassay; Fellowship; Foundations; Functional disorder; Future; Ganglia; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal tract structure; Genetic Transcription; Goals; Human; Immunoprecipitation; In Vitro; Incontinence; Individual; International; Intestines; Investigation; Lead; Location; Longitudinal cohort; Mass Spectrum Analysis; Measures; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mus; Muscle; Myenteric Plexus; Neurology; Outcome; Outcome Study; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patients; Pattern; Phenotype; Physiological; Proteins; Publications; Radioimmunoassay; Radiolabeled; Radionuclide Imaging; Reaction; Research; Rheumatology; Scientist; Scleroderma; Series; Severities; Stains; Subgroup; Surveys; Symptoms; Technology; Therapeutic; Tissues; Topoisomerase; Training; Translational Research; Translations; United States National Institutes of Health; Universities; Vasculitis; Western Blotting; Work; base; cellular targeting; clinical investigation; clinical phenotype; cohort; disease mechanisms study; gastrointestinal; gastrointestinal symptom; insight; mortality; motility disorder; neuromuscular; neuromuscular transmission; novel; novel therapeutics; outcome prediction; peripherin; prevent; professor; programs; relating to nervous system; response; rheumatologist; risk stratification; skills; voltage

PROJECT ABSTRACT Dr. Zsuzsanna McMahan is an Assistant Professor of Medicine in the Division of Rheumatology at Johns Hopkins University. She obtained her Masters in Clinical Investigation during her rheumatology fellowship training, and she is currently supported by the Johns Hopkins Clinician Scientist Development Award, the Jerome L. Greene Foundation, and the NIH Loan Repayment Program. Her co-primary mentors are Dr. Fredrick Wigley, an internationally recognized rheumatologist with expertise in scleroderma (SSc), and Dr. Livia Casciola-Rosen, an internationally recognized cell biologist with expertise in the identification of novel autoantibodies. Dr. Antony Rosen, the Director of the Division of Rheumatology, and Vice Dean for Research at Johns Hopkins, has significant expertise in translational investigation, and is also part of her mentoring team. Dr. McMahan created an outstanding Advisory Committee comprised of mentors and consultants who have specific areas of expertise which are relevant to the proposal. These include Drs. Michelle Petri (longitudinal cohorts) and Clifton Bingham (patient reported outcomes) in rheumatology, Dr. James Russell in neurology (autonomic dysfunction), and Dr. Jay Pasricha in gastroenterology (dysmotility). They will provide guidance specific to their area(s) of expertise. This Advisory Committee is highly enthusiastic about the proposal and fully invested in mentoring Dr. McMahan. The K23 award will enable Dr. McMahan to gain additional skills important for the conduct of translational research, develop expertise in the specific niche of neurogastroenterology as it pertains to SSc, and acquire the data and publications necessary to support a strong R01 application. In this proposal, Dr. McMahan seeks to precisely define anatomical subsets of SSc gastrointestinal (GI) dysmotility using a radionucleotide-based whole gut transit study, associate the GI dysmotility subsets with traditional SSc antibodies and antibodies that target neuromuscular transmission pathways, and finally define novel autoantigens targeted by SSc sera in the GI tract. Autoantibodies in SSc associate tightly with clinical phenotypes and serve as useful markers in risk stratification. Currently, risk stratification in SSc GI disease is limited, with few autoantibodies associated with GI complications. Clearly phenotyping GI subsets will provide a platform to study disease mechanism within more homogenous SSc GI subsets and provide a framework from which to explore novel therapies in the longer term. Dr. McMahan has generated strong preliminary data, which supports the following ideas: (1) specific patterns of GI dysmotility exist in SSc; (2) autoantibodies to neuromuscular transmission pathways are present in patients with SSc and may associate with specific GI outcomes; and (3) SSc sera from patients with dysmotility recognize distinct cellular subsets in the GI tract. She has established strong inter-departmental collaborations that will provide the required support and expertise to guide her and ensure the completion and appropriate interpretation of the proposed studies. The results of these studies will create a platform for future work aimed at evaluating biological mechanism, defining biomarkers of disease activity, and exploring novel therapies.

项目摘要

项目成果

Linaclotide for the treatment of refractory lower bowel manifestations of systemic sclerosis.

• DOI: 10.1186/s12876-021-01738-0
• 发表时间: 2021-04-15
• 期刊: BMC gastroenterology
• 影响因子: 2.4
• 作者: Dein EJ;Wigley FM;McMahan ZH
• 通讯作者: McMahan ZH

Gastrointestinal involvement in systemic sclerosis: an update.

• DOI: 10.1097/bor.0000000000000645
• 发表时间: 2019-11
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1

Clinical Assessment of Gastrointestinal Involvement in Patients with Systemic Sclerosis.

系统性硬化症患者胃肠道受累的临床评估。

• DOI: 10.18103/mra.v8i10.2252
• 发表时间: 2020
• 期刊: Medical research archives
• 作者: Kaniecki,Timothy;Abdi,Tsion;McMahan,ZsuzsannaH
• 通讯作者: McMahan,ZsuzsannaH

Experience with Esophagogastrointestinal Transit Scintigraphy in the Initial 229 Patients: Multiple Regions of Dysmotility Are Common.

最初 229 名患者的食管胃肠道闪烁扫描经验：多区域运动障碍很常见。

• DOI: 10.2967/jnumed.120.243527
• 发表时间: 2021
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Ziessman,HarveyA;Jeyasingam,Mathurika;Khan,AhsanU;McMahan,Zsuzsanna;Pasricha,PankajJ
• 通讯作者: Pasricha,PankajJ

A practical approach to the evaluation and management of gastrointestinal symptoms in patients with systemic sclerosis.

全身性硬化症患者的胃肠道症状评估和管理的实用方法。

• DOI: 10.1016/j.berh.2021.101666
• 发表时间: 2021-09
• 期刊: Best practice & research. Clinical rheumatology
• 作者: Kaniecki T;Abdi T;McMahan ZH
• 通讯作者: McMahan ZH