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Dr. Clarissa Craft awarded new NIH grant.
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Congratulations to Dr. Roberta Faccio, PhD for her election to The American Society for Bone and Mineral Research (ASBMR) Board of Directors as a Council Member and to Dr. Clarrisa Craft, PhD for her appointment to the finance committee. www.asbmr.org
Dr. Matthew Silva, PhD was named ORS Treasurer Elect for 2018-2019, will become treasurer 2019-2022 www.ors.org/board-of-directors

Citing the grant in publications:

“Washington University Musculoskeletal Research Center (NIH P30 AR074992).”

 

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Musculoskeletal Research Center

Over the past four years with the opportunity provided by the P30 CCMBM grant, our loosely organized set of musculoskeletal labs has developed into a well respected Musculoskeletal Research Center with 75 members from 22 Departments, over 250 publications (135 in Reporter), a new facility with 12 musculoskeletal labs co-localized with the Administration and Research Cores, an active and productive Pilot and Feasibility Program, a popular Musculoskeletal Seminar Series and well-attended Annual Symposia. Our fields of interest have covered a wide variety of common musculoskeletal disorders from osteoporosis to osteoarthritis to tendon injuries to cancer. We now have $59 million in funding with $35 million from the NIH, and were recently awarded a T32 Training grant in Skeletal Metabolic Diseases.

During the next five years, we plan to grow our Center to include a wider range of research interests stemming from our larger and more diverse research base, such as cancer metastasis to bone, scoliosis and intervertebral disc disease, tendon to bone healing, cartilage repair and stem cells in regenerative medicine. Our enrichment program will be expanded to include mentoring activities and training and education in specialized research techniques. The CCMBM enables the offering of many new services that will help drive the science of the research base, such as an expansion of the animal models to include zebrafish, isolation of specific populations of cells using histology and new non-invasive techniques to monitor tissue quality. With the help of the ICTS, we are very excited to include a new emphasis on translation of our animal research to the patient.

The CCMBM will continue to provide leadership in promoting quality research, foster collaborations and interdisciplinary approaches, expand the ranks of the research base and help drive the science of musculoskeletal investigators by providing increasingly sophisticated and powerful technologies through our research cores.

 


CORE A - ADMINISTRATIVE CORE

In the next five years, we plan to continue providing top-quality services to our Research Base and other investigators, while developing new cutting-edge technologies and programs, hinging upon the expertise and experience built in the past four years of activities. As a new direction, we will address an area of relative underachievement, i.e. the interaction between basic and clinical researchers, with the purpose of facilitating translation of basic and animal research to the clinic for the ultimate benefit of patients with musculoskeletal disorders.

Specific Aims of Core A for the next 5 years:
  • Aim 1 – Provide Leadership of the CCMBM, and Integrate Core Center Components and Activities
  • Aim 2 – Administer the Center Enrichment Program including a Pilot and Feasibility Grant Program, Musculoskeletal Seminar Series and Summer Educational Series, Annual Symposium and Holiday Party and Poster Session
  • Aim 3 - Communication with stake holders (E-Newsletter, Website)
  • Aim 4 – Coordinate Core Center Activities with other Programs including a mentoring program with the T32 Metabolic Skeletal Disorders Training Grant, Institute for Clinical & Translational Science, Center for Regenerative Medica and over Washinton University Core Facilities
  • Aim 5 – Promote Awareness and Exchange Information on the Translation of Research

CORE B - STRUCTURE AND STRENGTH

Since 2009, we have provided billable services to 59 investigators, who have reported structure or strength data in 68 manuscripts to date. We have presented seminars and developed online resources to advance understanding and promote best practices. We have invested in new approaches to enhance our capabilities. Finally, we moved and consolidated our major resources into a single floor of the new Musculoskeletal Research Center. To sustain and extend these accomplishments, we propose the following five objectives: 1) support cost-effective utilization of existing resources for densitometry, imaging, and mechanical testing; 2) maintain expert oversight and quality control; 3) provide training and enrichment opportunities (in concert with the T32 Washington University Metabolic Skeletal Disorders Training Program); 4) enhance Core capabilities through development of new techniques; and 5) foster new interactions and enhance existing interactions between members of the Research Base of the Core Center for Musculoskeletal Biology and Medicine (CCMBM).

Specific Aims of Core B for the next 5 years:
  • Aim 1 – Imaging: Maintain protocols and equipment, provide training and technical support, and perform imaging of musculoskeletal structures and tissues from animal models generated by Research Base investigators. Routine techniques include plane radiography, dual-energy X-ray absorptiometry (DXA), and micro-computed tomography (microCT), each available post mortem or in vivo. In the past funding period we developed magnetic resonance imaging (MRI) approaches for imaging non-mineralized tissues in mouse and rat, and will now make these available to the Research Base. We will continue to develop new approaches for imaging non-mineralized tissues (tendon, muscle, cartilage, disc). We will present regular seminars on imaging, and strengthen alliances with other imaging centers on campus. Rationale: Investigators in the Research Base have an ongoing need for musculoskeletal imaging. The Core is an efficient, cost-effective resource that addresses this need. We have the facilities and equipment in place and the Core personnel have demonstrated expertise for obtaining and analyzing quantitative data. Core center funding (supplemented by user fees) will support technical staff supervised by the Core Directors to perform image acquisition and analysis, provide training to users, and develop new approaches. Our goal is to provide optimal access and utilization of existing resources while ensuring quality control via adherence to best practices.
  • Aim 2 – Mechanical Testing: Perform mechanical testing to assess the functional properties of musculoskeletal structures and tissues from animal models generated by Research Base investigators. Standard testing methods include long-bone bending, vertebral compression, tendon and tendon-to-bone tensile testing. During the past funding period we developed microindentation testing methods, and will now make these available to users. Because mechanical testing has been less widely utilized than imaging, we aim to increase the number of users by 50% during the next 5 years. We will present seminars and provide training and enrichment to enhance understanding of biomechanics among CCMBM investigators. Rationale: Investigators in the Research Base have a need for mechanical testing to assess functional properties of musculoskeletal tissues and structures. We have facilities and equipment and protocols in place and the Core personnel have demonstrated expertise for obtaining and analyzing mechanical data. Core center funding (supplemented by user fees) will support technical staff supervised by the Core Directors to perform testing using existing protocols and to develop new protocols as required.

In summary, Core B will provide critical support to members of the Research Base to enable cost-effective utilization of methods to quantify morphology and mechanical properties from musculoskeletal tissues. Through our efforts we will enhance research productivity and provide access to state-of-the-art and emerging techniques.


CORE C - HISTOLOGY AND MORPHOMETRY

The strength of Core C lies in our expert staff, quality control, and close communication with investigators at all stages of their projects to ensure optimal histology-based analysis. In its first 4 years of operation, the Core has adapted to the needs of its investigator base, and this will be continued in the future as it is critical to our success. Importantly, this Core complements the specific functional analyses proposed in Core B and the animal new models generated by Core D.

Specific Aims of Core C for the next 5 years:
  • Aim 1 - Deliver high-quality, standard histological sections routine and specialized stains for all musculoskeletal tissues (bone, cartilage, tendon, ligament, muscle), including paraffin, methylmethacrylate, and frozen (OCT) embedding and specific tissue orientations. This approach allows investigators to take an initial observation such as bone fragility or muscle weakness and progress to a mechanistic understanding through cell-specific analysis.
  • Aim 2 - Provide specialized histology techniques including nondecalcified frozen sections with tape transfer for fluorescent label visualization, immunostaining, in situ hybridization or laser capture microdissection. In addition to sectioning services, training and protocols for immunostaining and in situ hybridization will also be provided. The Core will collaborate with Users to incorporate new procedures and protocols as needed.
  • Aim 3 - Provide equipment and training for histomorphometry for quantitative analysis of bone and cartilage. In addition to maintaining a BioQuant Osteo II histomorphometry system, the Core will provide protocols and training for its use. Consultation services will be provided to optimize quantitations for specific disease models such as fracture, metastasis, and arthritis.
  • Aim 4 - Provide education to entire user base in the area of experimental design and interpretation of histological methods, current standards of practice (especially for histomorphometry), and services available through the Core. Education will be provided to users via group meetings, through the Summer Educational Series, focusing on Core services and techniques and through the Skeletal Biology and Pathophysiology Series. This educational aim is integrated with the T32-funded Washington Metabolic Skeletal Disorders Training Program.

In summary, the Musculoskeletal Histology and Morphometry Analysis Core will continue to provide state-of-the-art services in histology-based methods to analyze bone, cartilage, tendon, ligament and muscle to our Research Base in an accessible, collaborative, and cost-effective manner developing new technologies when appropriate and expanding tissue expertise to zebrafish and human samples.


CORE D - GENETIC MOUSE MODELS

Mouse genetic models have been extensively utilized by CCMBM investigators and are central to research in musculoskeletal biology and medicine. The Animal Models Core will facilitate the implementation of new technology, and the production, acquisition, and sharing of pertinent mouse genetic models among CCMBM investigators as well as provide training and education for non-expert users. To foster a state-of-the-art research environment for CCMBM researchers, the Animal Models Core (Core D) will work to support the optimization and implementation of new technologies, the generation of mouse genetic tools that will have wide use among CCMBM researchers, the production, preservation, and sharing of genetically altered mice in a timely and reliable manner, and the exploration of the zebrafish as a model for musculoskeletal research.

Specific Aims of Core D for the next 5 years:
  • Aim 1 - Consultation and Education on Mouse Genetic Models. We have great expertise in generating and analyzing mouse and zebrafish genetic models and we have initiated programs to educate and facilitate knowledge transfer among CCMBM researchers. This aim will continue and enhance very successful educational programs that were implemented during the past four years by continuing to advise and educate new and non-expert users on state-of-the-art and emerging technologies, mouse and zebrafish genetic strategies, target and transgene design, as well as colony management.
  • Aim 2 - Production of Novel Genetic Tools and Models to Support Research on Musculoskeletal Diseases. This aim has two components designed to implement emerging technology, generate novel genetic tools to advance musculoskeletal research, and foster the development of investigator-initiated generation of novel mouse models. Aim 2a will develop TAL Effector Nuclease (TALEN) technology for gene targeting in mice and advance the technology to allow efficient re-engineering of established mouse knock-in alleles. We will generate and validate universal TALEN vectors to modify existing alleles, such as the ROSA26 locus and Cre and LacZ knock-in alleles. This will benefit Musculoskeletal P30 members by enabling fast and costeffective production of new mutant mice and modification of well–characterized existing lines with defined temporal and spatial expression patterns. Aim 2b will focus on helping core investigators generate specific mouse models. The investigator will initiate a project by identifying the desired mouse models. For ES cell knock-out studies, the investigator will either acquire targeted ES cells from the International Knock-out Mouse Consortium (IKMC), or generate targeted ES cells with core guidance and technical support from the existing Transgenic Vector Core (TVC) and Murine Embryonic Stem Cell Core (ES Core). Alternatively, novel TALEN (and CRISPR/Cas) technology, being developed by the TVC can be implemented. For DNA injection, the investigator will provide the transgene or TALEN construct. Microinjections of either correctly targeted ES cells or DNA/RNA constructs will be performed at the existing Mouse Genetics Core (MGC). All existing core facilities are well established and have excellent track records in supporting mouse transgenic studies.
  • Aim 3 - Develop the Use of Zebrafish Models in Musculoskeletal Research. For many biological and medical questions, the zebrafish has become an optimal model of development and disease. The zebrafish offers many advantages for basic developmental and disease studies, including rapid external development of transparent embryos, susceptibility to mutagens, and the ability to knockdown endogenous gene expression and introduce transgenes into the germline. TALEN and CRISPR technologies are well advanced in zebrafish. We have a unique opportunity to offer the services of our new highly automated large Zebrafish Core Facility to our Research Base. Dr. Lila Solnica-Krezel, the new Chair of Developmental Biology, established the facility in 2011, thus opening the way for large-scale use of zebrafish as a model system at Washington University. Education and access to this exciting resource will be provided under the direction of Dr. Stephen Johnson.
  • Aim 4 - Establish and Maintain a Campus-wide Database for Mouse and Zebrafish Strains. A large number of transgenic and knock-out mouse strains are being used by Washington University investigators. We have initiated a database of available mouse lines over the past four years. In this aim we will continue to maintain, expand, and publicize this database and add new mouse strains and zebrafish mutants to facilitate reagent sharing within the musculoskeletal community at large.

In summary, the Animal Models Core is designed to enhance the ability of our research community to develop novel mouse genetic tools and models and, in the future, zebrafish, and maximize the benefit of existing mouse genetic and zebrafish resources through advancing technology, providing education and advice, and where possible, subsidizing the cost of a limited number of lab-specific projects.