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Se-Jin Lee, MD, PhD, Johns Hopkins University School of Medicine (Baltimore, MD)
Background : Multi-atlas segmentation is a powerful method for automatic structural segmentation of several sub-structures in many organs. However, no study has used this method so far for skeletal muscle segmentation. In this study, we present a fully automatic multi-atlas segmentation pipeline we have developed for segmentation of quadriceps muscles from magnetic resonance images obtained in twenty five young healthy males.Materials and Methods: A non-linear registration process based on ANTs algorithm was applied to thigh images initially automatically segmented for bone, muscle and fat tissues. Optimized fusion parameters of STEPS multi-atlas segmentation were determined to obtain the highest DICE index as compared to the manual segmentation of quadriceps muscles, considered as the gold standard. Validation and reproducibility of the pipeline was assessed on two other databases of seven healthy male subjects.Results: Results for each quadriceps muscle show a mean DICE similarity coefficient higher than 0.85.Conclusion:Through some examples, we show the robustness of this registration method for the longitudinal follow-up of atypical healthy subjects and dytrophic patients.
Maggie Curtis, MA
Program Coordinator
As Program Coordinator, Maggie works closely with the Jain Foundation Scientific Advisory Board to schedule and track project tasks, ensuring that key milestones are met. She brings more than 20 years of experience in administration, operations and marketing communications. Creating new tools and processes that help others meet their goals is her passion.
She earned a Masters in English from the University of Wisconsin, with a focus on organizational communication.
Maggie joined the Jain Foundation in 2023.
The typical paradigm is that new technologies in medicine transition from the laboratory (Bench) through several steps towards eventual use to treat patients (Bedside). But clinical and genetic studies have a lot to teach us about dysferlinopathy and can inform research projects looking for new treatments. This webinar included overviews of the clinical phenotype and genetics of dysferlinopathy, and also highlighted some of the findings of recent clinical studies, in particular the Clinical Outcome Study in Dysferlinopathy (COS), as well as large-scale sequencing studies that document the spectrum of mutations of the DYSF gene and carry implications about the role of the dysferlin protein in muscle biology.
Recent discoveries show how dysferlin deficiency affects cellular metabolism and how diet and exercise may affect the course of dysferlinopathy. Metabolic changes in skeletal muscle are a hallmark of several types of muscular dystrophy. In vitro and in vivo studies of dysferlinopathy have identified metabolic effects are often distinct or at odds with observations from other types of muscular dystrophy. This indicates that some metabolic changes may be unique to dysferlin deficiency rather than being caused by generic dystrophic processes. This webinar included findings from metabolic studies on dysferlin-deficient muscle fibers, and the impact of dietary interventions on the phenotype of dysferlinopathy.
This webinar covered a variety of recent results across several topics related to dysferlin and dysferlinopathy – from research tools to big data analysis, to the latest insights on protein structure, to therapeutic strategies. Several laboratories presented findings that the Jain Foundation had been following with great interest, but which were not published yet. We felt that sharing these results through this webinar (which can be thought of akin to a “late breaking developments” session at a scientific conference) would be extremely valuable to the entire dysferlin research community.
If you were unable to attend the webinar, but are interested in viewing the recording, please contact the Jain Foundation at admin@jain-foundation.org
Kanan Lathia, MS
Associate Director of Research
Kanan Lathia earned her Masters in Biochemistry and Molecular Biology from OHSU, Portland. Her masters’ thesis was on Drug Repurposing in Muscular Dystrophy. She has worked on various large-scale, ambitious projects that yielded impactful data in ALS, Oncology and Brain Science.
Kanan joined Jain Foundation in 2023 as an Associate Director of Research and is a member of Jain Foundation Scientific Advisory Board. She is responsible for monitoring funded projects; ensuring achievements and progress of these projects. She also collaborates with senior members in soliciting proposals from various laboratories working in dysferlin field. She enjoys yoga and dancing
Destructive Muscle Inflammation: Are Proliferating Macrophages the Culprit in Dysferlinopathy?
Vicki R Kelley1, Jea-Hyun Baek1
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 2
Macrophages (Mø) are prominent in skeletal muscles in patients with dysferlinopathy. Mø exert diverse functions; integral in both tissue repair and destruction. We initially tested the hypothesis that Mø are defective in shifting from M1-like “inflammatory/destructive” to the M2-like “reparative/regulatory” phenotype in advancing dysferlinopathy. Our preliminary data indicates that in dysferlin-deficient B6.A-Dysfprmd/GeneJ (BLA/J) mice with advancing dysferlinopathy: (1) Mø are skewed towards M1-like (express TNF-a and iNOS), compared to the M2-like (express TGF-b, IL-10 and Arginase) phenotype; (2) Mø comprise the vast majority of proliferating cells; (3) proliferating intra-muscle Mø robustly expressing TNF-a and iNOS, rather than TGF-b, IL-10 and Arginase; and (4) proliferating Mø are adjacent to necrotic muscle fibers. These findings are in stark contrast to the abundance of proliferating M2-like, not M1-like, Mø adjacent to necrotic muscle fibers during repair. We hypothesize that an unchecked expansion of M1-like Mø likely drives unrelenting muscle injury that advances dysferlinopathy. Using genetic fate mapping and in vitro experiments we are determining whether the absence of dysferlin in Mø and/or muscle is responsible for promoting Mø infiltration, proliferation and skewing towards M1 that drives non-resolving, destructive muscle inflammation. Detailing the Mø-mediated mechanisms instrumental in the pathogenesis of dysferlinopathy is likely to uncover novel therapeutic strategies for this illness.
Availability:
The Jackson Laboratory
Stock number: 012767
Strain information: http://jaxmice.jax.org/strain/012767.html
Phone: 800-422-MICE (800-422-6423)
610 Main Street, Bar Harbor, Maine 04609 USA
Please note that this strain has been cryopreserved by the Jackson Laboratories, but the Jain Foundation maintains a private colony of these mice for public use. To obtain these mice, please contact the Jain Foundation:
Jain Foundation Inc.
9706 Fourth Ave NE, Suite 101
Seattle, Washington 98115
Phone: 425-882-1492
Fax: 425-882-1050
Email: admin@jain-foundation.org
Development:
In these mice the progressive muscular dystrophy (prmd) allele from the A/J inbred strain is crossed onto the C57BL/6 genetic background. The cross was performed in the laboratory of Dr. Isabelle Richard at Genethon and the backcross generation reached N8. In collaboration with the Jain Foundation, Dr. Richard donated the strain to The Jackson Laboratory in 2010. Upon arrival, mice were bred to C57BL/6J for at least 2 generations to establish the colony.
Mutation:
An ETn retrotransposon (5-6kb) is inserted in intron 4 of the dysferlin gene.
Symptoms:
Disease onset is observed by 2 months and is characterized by the presence of centronucleated fibers and areas of inflammation. As seen with the original background A/J, mice homozygous for the prmd allele on the C57BL/6J background display an increasing number of centronucleated fibers and impairment in the majority of muscles by 4 months of age. In order of severity, the most affected muscles are psoas, quadriceps femoris, tibialis anterior, and gastrocnemius. Mice exhibit a decreased membrane repair capacity following laser wounding experiments. In an open space assay, mice cover less distance and are less active than wild-type. Mice that are homozygous for this allele are viable, fertile and normal in size.
Comparison with other disease strains:
Disease progression is similar to A/J: slightly slower than in SJL/J, Dysf-/- (Campbell), Dysf-/- (Brown), and C57BL/10.SJL mice. As in both SJL/J and Dysf-/- (Brown) mice, proximal muscles are more severely affected than distal muscles. As in Dysf-/- (Brown) mice, abdominal muscles are also affected.
Control strain(s):
C57BL/6 (for homozygotes); littermates (for heterozygotes).
References:
Lostal W; Bartoli M; Bourg N; Roudaut C; Bentaib A; Miyake K; Guerchet N; Fougerousse F; McNeil P; Richard I. 2010. Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum Mol Genet 19(10):1897-907.
Human Dysferlin protein - Human dysferlin protein purified by Dr. Bryan Sutton's lab is available. To obtain the human dysferlin protein contact the Jain Foundation at admin@jain-foundation.org.
Human Biospecimens – Plasma, serum, DNA, RNA, fibroblasts, cell lines, and biopsy material from genetically confirmed dysferlinopathy patients
Data Resources – natural history clinical data sets, miRNA, RNA, protein, and cytokine data sets, and mouse proteomic and lipidomic data sets
Study Recruitment – support for recruiting dysferlinopathy patients out of the Dysferlin Registry for surveys, studies, and clinical trials
Pre-proposals
Clinical testing and Diagnostic support
Development of Standards of Care
Patient and Physician Education - LGMD Masterclasses, Patient Educational Series, Healthcare Professionals FAQ, Automated LGMD Diagnostic assistant (ALDA)
Dysferlin Conferences and Webinars – We frequently gather experts from around the world to discuss to discuss the state of the field, come up with solutions to challenges, and identify new directions to pursue
Jain Foundation Scientific Advisory Board (SAB) – The SAB, an in house team of motivated and focused individuals with strong scientific backgrounds, has deep understanding of dysferlinopathy and are willing and available to answer any questions or discuss any potential research project
Research grants – We provide funding for basic, translational, and clinical research from academia and industry that align with our goals
Research tools – From cell lines to antibodies to animal models and DNA constructs, the Jain Foundation has worked hard to create and gather all the tools necessary to study dysferlinopathy
Preclinical platform – The Jain Foundation has developed an MRI platform for the evaluation of potential therapeutic intervention in mouse models of dysferlinopathy
Natural History and Clinical Study Data – The Jain Foundation has funded a natural history of study of over 200 genetically confirmed dysferlinopathy patients. The data from this study is available to both academia and industry
Summary: A number of findings have come to our attention at the Jain Foundation highlighting a connection between dysferlin and lipid storage, transport, and metabolism. These observations include recent publications as well as unpublished results from current research projects, involving a wide range of different observations. We feel these data, taken together, are telling us something important about dysferlin’s role in muscle health—but we aren’t sure what that is. For this reason, we think it’s important for the research community to see and discuss the recent results on dysferlin and lipids and generate hypotheses and ideas for future studies. We had planned a session devoted to this topic in the Dysferlin Conference that was scheduled to take place in March 2020. Due to the in-person conference’s postponement caused by the COVID pandemic, we decided to hold a webinar over two days, featuring findings from several labs on the dysferlin/lipid connection, with time for the community to discuss the observations and their implications.
Summary: Cells typically maintain very low levels of intracellular calcium, as it is used for a variety of signaling and proteolytic functions. For muscle fibers, however, a large calcium release from the endoplasmic reticulum initiates contraction, necessitating specialized calcium-handling adaptations in muscle. There is increasing evidence that dysferlin is part of muscle fibers’ calcium management system, as studies from different laboratories have shown that muscle’s calcium handling is altered in dysferlin’s absence. Dysferlin is known to bind calcium via its C2 domains and changes its behavior in terms of binding to lipids, to itself, and to other proteins at elevated calcium concentration. This was noted in the context of dysferlin’s role in membrane repair, where an increased calcium concentration occurs due to diffusion from the cell’s exterior. Dysferlin’s role in regulating calcium, however, appears to be broader, and extend to managing intracellular calcium during contraction. This webinar presents recent work from several research groups which offers clues to dysferlin’s role in managing calcium, and the effect on muscle fibers’ calcium handling when dysferlin in absent.
The Jain Foundation Scientific Advisory Board is unique in that it consists of an entirely in-house team of motivated and focused individuals with strong scientific backgrounds. There is no external advisory board. All proposal reviews and funding decisions are carried out exclusively by the in-house team.
The members of the Jain Foundation team have PhDs in biology-related fields and significant laboratory experience. In order to join the Foundation, they have abandoned the traditional path of an experimental biologist and no longer have any conflicting interests in academic science. For brief biographies of the team members, please visit our team. The Jain Foundation team's role includes and surpasses that of a typical Scientific Advisory Board: they identify the most pressing scientific questions in the dysferlin field, often design specific experiments to address these questions, identify and solicit proposals from laboratories with the expertise to perform the necessary experiments, and monitor the progress of the projects.
Having a team dedicated to one cause has enabled the Jain Foundation to become a center of excellence, capable of a comprehensive and real time assessment of the state of the field with the means to foster collaborations between previously isolated researchers.
The Wellstone Muscular Dystrophy Specialized Research Center at the University of Iowa has a repository of a broad spectrum of skeletal muscle biopsies from neuromuscular diseases patients including those with dysferlinopathy. Click here to obtain information on how to request these samples.
Skin fibroblasts were obtained from a skin biopsy from 71 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS). These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom. Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application. Correlation with clinical measures obtained over the 3-5 years of the study are also available (see information in Data Resources). For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.
RNA was obtained from 160 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS). These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom. Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application. Correlation with clinical measures obtained over the 3-5 years of the study are also available (see information in Data Resources). For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.
Genomic DNA was obtained from 160 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS). These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom. Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application. Correlation with clinical measures obtained over the 3-5 years of the study are also available (see information in Data Resources). For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.
Yearly plasma and serum aliquots were obtained from 150 genetically confirmed dysferlinopathy patients participating in the International Clinical Outcome Study for Dysferlinopathy (i.e. COS). These samples are available by request from the MRC Biobank for Rare and Neuromuscular Disease in Newcastle, United Kingdom. Contact the biobank at jwmdrc.biobank@newcastle.ac.uk to request an application. Correlation with clinical measures from the same time period is also available (see information in Data Resources. For help determining the most appropriate samples to obtain for your research needs contact the Jain Foundation at admin@jain-foundation.org.
Proteomic and lipidomics data sets are available from the evaluation of the quadricep muscles of 18wk old mice wild-type versus dysferlin deficient Bla/J mice. This data was developed by Dr. Frances Lemckert. To request access to this data contact Dr. Lemckert at frances.lemckert@sydney.edu.au.
Data sets are available from the evaluation of dysferlinopathy patient samples for possible miRNA, mRNA, protein, and cytokine blood based biomarkers. This data was obtained through a collaboration between the Jain Foundation and PROOF Centre of Excellence based in Vancouver, BC Canada. To request access to this data please contact the Jain Foundation at admin@jain-foundation.org.
200+ genetically confirmed dysferlinopathy patients were recruited for the International Clinical Outcome Study of Dysferlinopathy (i.e. COS), which evaluated them over 3-5 years. A combination of medical, physiotherapy, laboratory, MRI, patient questionnaires and patient reported outcome measures (PROMS) were performed on each participant according to their level of ability. Requests for this data should be directed to Heather Hilsden at heather.hilsden@newcastle.ac.uk. Click here for links to publications on the COS data. For help determining the most appropriate data to request for your research needs contact the Jain Foundation at admin@jain-foundation.org.
Laurie Long
Office Management and Study Coordination
Ms. Long brings a depth of knowledge and a comprehensive skill set stemming from over 25 years’ experience in administrative and operations support positions. She plays a critical role in maintaining accuracy, preparedness and reputation that have been established by the Jain Foundation in the field of dysferlin research. Ms. Long coordinates logistical operations at the office as well as finance, project management and study coordinating. Her passion for technology is utilized in day to day tech support as well as with the patient registry software.
Ms. Long joined the Jain Foundation team in 2016.
Joshua Thayer, Esq.
General Counsel
Mr. Thayer earned his J.D. from Boston College Law School and his A.B. from Harvard University, where he studied the Soviet political system and Russian language, literature and history. As General Counsel of the Jain Foundation, Mr. Thayer is responsible for providing his scientific and management colleagues with effective advice on company strategies and their implementation, and for drafting and negotiating a variety of operational agreements, including license agreements, clinical trial agreements, research funding agreements, and service agreements.
Prior to joining the Jain Foundation, Mr. Thayer was a partner in the Business Law Department of Edwards Wildman Palmer, which has become a part of Locke Lord since his departure. Mr. Thayer has over 22 years of experience as a corporate transactional lawyer advising clients within the life sciences industry at all stages of their development. He has a broad background in general corporate representation, venture capital financing, mergers and acquisitions, public offerings and securities law compliance, with a particular focus on licensing transactions among biotechnology and pharmaceutical companies. Mr. Thayer has also worked extensively with the technology transfer offices of universities, hospitals and other research institutions.
Bradley Williams, PhD
Director of Research & Diagnostic Innovation
Dr. Williams earned his Ph.D. in Applied Physics from Cornell University and previously worked as a physicist at the Naval Research Laboratory in Washington, DC. He is also a self-taught expert on dysferlinopathy and has a long history of involvement in the dysferlin field. He created the first website about dysferlin deficiency in 2001.
Dr. Williams has been an advisor to the Jain Foundation since its inception in 2005 and joined the foundation full time in 2015. His extensive knowledge of the key players and findings in the dysferlin field has been an invaluable resource for foundation. Dr. Williams serves as a member of the Jain Foundation Scientific Advisory Board and provides advice primarily on projects related to medical physics, promising therapeutic drug candidates, patient diagnosis, and dysferlinopathy disease progression / natural history. He also assists with interactions, education, and recruitment of individuals with dysferlinopathy through various social media platforms.
Akshay Jain
Chairman and CEO
Akshay Jain cofounded the Jain Foundation with his father Ajit in 2005 after being diagnosed with dysferlinopathy in 2001. He attended NYU with a focus on finance. In addition to being the CEO and Chairman of the Board, Akshay manages the endowments of the Foundation.
Sarah Shira Emmons, MPH
Vice President of Patient Affairs and Community Strategies.
Sarah Shira Emmons earned a Master of Public Health degree from the University of Washington, School of Public Health, with a focus on Health Systems, and Population Health. Her research involved exploring behavior change theory through clinical and community-based programs serving oppressed communities and conducting qualitative research, investigating the clinical experiences of individuals with dysferlinopathy.
Ms. Shira Emmons leads and implements the Jain Foundation's patient identification and engagement efforts globally. She interacts extensively across sectors to expedite diagnostic support, inter-collaborator connection and to align all community members for successful clinical trials for dysferlinopathy. She develops and manages the foundation’s Dysferlin Registry, guides clinical research projects, designs engagement strategies, and conceptualizes initiatives to amplify the impact of the foundation.
Laura Rufibach, PhD
Co-President
Dr. Rufibach earned her Ph.D. in Molecular and Human Genetics from Baylor College of Medicine, where she studied genotype/phenotype correlations and identified new disease genes for a form of peripheral neuropathy. Her postdoctoral research at the University of Washington centered on the identification of structure/function relationships in dystrophin and how that information could be used to construct mini-dystrophin vectors for use in gene therapy in Duchenne muscular dystrophy.
Dr. Rufibach is a senior member of the Jain Foundation Scientific Advisory Board, which is responsible for implementing the strategic goals of the foundation, identifying the most pressing scientific questions in the dysferlin field, designing experiments to address these questions, identifying and soliciting proposals from laboratories with the expertise to perform these experiments, actively monitoring the progress of funded projects, and fostering collaborations between previously isolated researchers. In addition to her role on the advisory board, Dr. Rufibach oversees the foundation’s patient and physician outreach efforts, implements the foundation’s legal requirements, and leads the foundation's clinical efforts, including directing the upcoming clinical outcome study of dysferlinopathy and determining the best therapeutic candidates for clinical trials.
Doug Albrecht, PhD
Co-President
Dr. Albrecht earned his Ph.D. from the University of California, Los Angeles, where he studied muscle adaptation and remodeling. His postdoctoral research focused on the signaling aspects of the dystrophin cytoskeletal scaffold at the University of North Carolina at Chapel Hill and the University of Washington.
Dr. Albrecht is a senior member of the Jain Foundation Scientific Advisory Board, which is responsible for implementing the strategic goals of the foundation, identifying the most pressing scientific questions in the dysferlin field, designing experiments to address these questions, identifying and soliciting proposals from laboratories with the expertise to perform these experiments, actively monitoring the progress of funded projects, and fostering collaborations between previously isolated researchers. In addition to his role on the advisory board, Dr. Albrecht is also leading the foundation‘s assay development and preclinical analysis efforts, which are being conducted in partnership with contract research organizations.
Below is a quick summary of the inclusion/exclusion criteria. Please review this information carefully prior to making any decision regarding participating.
Inclusion Criteria:
Exclusion Criteria: