Musculoskeletal Research Training Program (T32)

The strengths of musculoskeletal research at the University of Minnesota are in the areas of basic discovery, mechanisms of musculoskeletal disease in animal models and outcomes-based research of standard clinical treatments. These strengths are found in the four primary focus groups. 

These focus groups allow for and encourage cross-disciplinary interactions between molecular biologists, (stem) cell biologists, orthopaedic surgeons, veterinary researchers and bioengineers. The primary interests of each faculty member guided his/her placement into the groups; however, many faculty members make significant contributions to more than one focus group.

Musculoskeletal Cancer Biology and Therapeutics

(D.R. Clohisy,* M. Garwood, D. Largaespada, J. Modiano)

The collective focus of this group is to understand the etiology, progression and clinical sequelae of musculoskeletal cancers and to develop new therapies for treatment and prevention; specific areas of research include the cellular mechanisms regulating osteolysis in cancer; bone cancer-associated pain and tumor metastasis to bone; animal models of sarcoma; clinical epidemiology research in osteosarcoma and rhabdomyosarcoma; and the development of new techniques in MR imaging and oncology.

Osteoarthritis and Cartilage Biology Group

(C. Carlson,* J. Bechtold, P. Ludewig, G.E. Pluhar)

This group has a common interest in understanding the etiology and treatments of osteoarthritis. Specific areas of research include the development and validation of animal models of osteoarthritis; bone fracture repair; biomechanics of the shoulder joint; and the pathophysiology of degenerative osteoarthritis of the spine.

Musculoskeletal Development Group

(R. Gopalakrishnan, D. Kaufman, K. Mansky, L. Potter, M. O'Connor)

This group is unified by the common interest of understanding the molecular mechanisms that regulate skeletal development, maturation, and differentiation. Specific areas of research include osteoblast and osteoclast biology and the role of these cells in the physiologic and pathophysiologic formation of the skeleton; mechanisms involved in limb regeneration in xenopus tadpoles; skeletal aberrations occurring in dwarfism; and estrogen signal transduction cascades in bone metabolism and cancer biology.

Epidemiology and Clinical Outcomes Research Group

(L. Spector*, M. Swiontkowski)

This group of investigators applies state-of-the-art epidemiologic and clinical outcomes research methodologies to critically evaluate a wide variety of musculoskeletal treatments. This group has multiple strengths but the two most important are their access to large patient/sample populations through cooperative multi-institutional trials and their international reputation in orthopaedic-based clinical outcomes research. Specific areas of research include the assessment of functional outcomes for the treatment of musculoskeletal conditions and the etiology and behavior of musculoskeletal cancers.

Leadership & faculty

Predoctoral

Liz Gacek

Department: Biomedical Engineering
Mentor: Victor Barocas, PhD
Description: My research focuses on mechanically characterizing and computationally modeling the lumbar facet
capsular ligament (FCL). I hope to better understand the mechanical environment that the FCL functions in
situ by merging microstructural tissue characteristics with macroscale kinematics in a multiscale model that
mimics realistic FCL material properties. Ultimately, I hope to develop a tool that accurately captures lumbar FCL
mechanics and furthers our understanding of what causes lower back pain.

 Emily Pope

Department: Veterinary and Biomedical Sciences
Mentor:David Largaespada, PhD
Project Description: Osteosarcoma is the most common primary bone tumor in humans and dogs.  The addition of multi-agent chemotherapy to treatment increased the human 5-year survival rate from less than 50% to 65-70%.  Previous work demonstrated that most patients have micrometastases at diagnosis but are successfully treated.  However, when a patient presents with macrometastases, long term survival drops precipitously to less than 20%.  Neoadjuvant chemotherapy is administered to improve surgical resection outcomes, but we hypothesize that this may trigger extracellular matrix (ECM) remodeling in a subset of metastatic cells that prevents chemotherapy and immune cells from penetrating into the tumor.  My research focuses on characterizing adaptations in the ECM and tumor microenvironment in response to chemotherapy. Using a mouse model of spontaneous osteosarcoma metastasis, my research specifically aims to improve therapeutic outcomes through targeting components of the ECM, increasing treatment efficacy and improving survival outcomes.

Gaura Saini, PT

Department: Rehabilitation Medicine
Mentor: Paula Ludewig, PhD, PT
Project Description: As a physical therapist, I am interested in clinical movement analysis and how movement impairments relate to pain. Specifically, my research will test how anticipated patterns of muscle activation based on movement patterns identified using biplane fluoroscopy correlate to quantitatively observed muscle activity. The goal of this research is to lay the foundation for developing specific muscle exercise interventions based on movement impairments. 

Postdoctoral 

 

Shawn Mahmud, MD, PhD

 

Department: Pediatrics, Division of Pediatric Rheumatology

Graduate Program: Pediatric Rheumatology Fellowship, Pediatric Physician Scientist Training Program (PSTP)

Mentor(s): Marc Jenkins, PhD, and Bryce Binstadt, MD, PhD

Project Description: My fellowship research interests center on further understanding the breakdown of tolerance in human autoimmune diseases.  In particular, I would like to learn to identify, track, and characterize rare, autoreactive T and B cells to understand how they cause autoimmunity. My interest has come from my experiences as a pediatric rheumatology fellow in treating patients with rheumatic conditions, such as juvenile idiopathic arthritis, systemic lupus erythematosus, and mixed connective tissue disease.  Although newer biologic medicines have transformed the care of these patients, these therapies are still relatively non-specific from an immunologic perspective in that they can affect many populations of immune cells. By learning to suppress only specific clones of autoreactive T and B cells, we may be able to protect patients from some of the unintended consequences of non-specific immunosuppression, chiefly infection. In the Jenkins lab, I am developing humanized mouse models (immunodeficient mice transplanted with human blood stem cells) to study autoreactive T and B cells relevant to human autoimmune diseases such as rheumatoid arthritis and mixed connective tissue disease. I am using novel peptide:MHC II tetramers to track CD4+ T cells in these models and understand how tolerance to self-epitopes breaks down. We hope these reagents may be directly useful for future studies of human patients and could help pave the way to developing antigen-specific immune therapies.  

 

 Christiana Raymond-Pope, PhD

 

Department: School of Kinesiology
Graduate Program: Kinesiology and Exercise Physiology
Mentor(s): Sarah M. Greising, PhD
Project Description: My current research examines the musculoskeletal system following complex orthopedic and volumetric muscle loss (VML) injury. VML occurs when there is traumatic orthopedic injury or surgical removal of skeletal muscle, often concomitant with bone fracture and loss of intramuscular neural and vascular structures, resulting in long-term functional disability. Using preclinical VML injury animal models, my research specifically aims to examine the therapeutic efficacy of a regenerative approach using bioengineered collagen scaffolds loaded with growth factors to promote organized skeletal muscle repair and, potentially, improved muscle function. Additional research pursuits include evaluating changes in the mass and function of the bone adjacent to the VML defect, as well as examining musculoskeletal outcomes in response to treatment incorporating a combined regenerative (e.g., scaffolds, growth factors) and physical rehabilitative approach following VML injury.

Predoctoral

Laura Antos, PhD 
Project: Characterizing ATP's effect on natriuretic peptide receptors in relation to long bone growth using fibroblast cell cultures.
Mentor: Lincoln Potter, PhD

Emily Bermel
Project: My research deals with the lumbar facet capsular ligament (FCL). The FCL guides and constrains spinal motions such as flexion/extension, lateral bending, and axial rotation. It is comprised of highly aligned collagen fiber bundles on the posterior surface and nonaligned elastin fibers on the anterior surface. My goal is to develop a theoretical/computational model of the degeneration process using growth and remodeling theories in conjunction with realistic models of the tissue geometry and properties. 
Mentor: Victor Barocas, PhD

Charles Billington, PhD 
Project: Examine the spectrum of craniofacial malformations resulting from mutation of the gene Twisted Gastrulation.
Mentor: Anna Petryk, MD

Nicholas Blixt
Project: I am researching the molecular mechanisms behind how histone deacetylase enzymes regulate osteoclast differentiation. The end goal of this research is to provide mechanistic insight into controlling osteoclast differentiation as potential new therapy for osteoporosis or other diseases characterized by uncontrolled bone loss. This compliments my main research interests, which involve elucidating the transcriptional and epigenetic profiles among cell types that produce and maintain the skeletal system, as well as how the skeleton is modeled and remodeled based on the activity of these cells. 
Mentor: Kim Mansky, PhD

Christina Brakken-Thal, PhD 
Project: To understand how Decapentapolegic (Dpp), a BMP protein, is regulated to pattern the dorsal surface of the embryo.
Mentor: Michael O'Connor, PhD

Aaron Broege, PhD 
Project: To determine how delta EF1 regulates osteoblast development.
Mentor: Michael Sanders, PhD

Amy Claeson, PhD
Project: Develop a multi-scale understanding of the structure and mechanical properties of the lumbar facet capsular ligament (FCL) at the spinal, segmental and tissue levels
Mentor: Victor Barocas, PhD

Brandon Diessner, PhD
Project Description: My research focuses on sarcoma etiology and outcomes in pediatric and young adult populations. I am particularly interested in identifying genetic variants that predispose individuals to osteosarcoma and Ewing sarcoma development, as well as identifying risk factors for metastatic disease at diagnosis. 
Mentor: Logan G. Spector, PhD

Aaron Edmund, PhD
Project: My research is focused on mechanisms of activation and inactivation of natriuretic peptide receptors
Mentor: Lincoln Potter, PhD

Arin Ellingson, PhD 
Project: To measure the helical axis of motion of lumbar spinal motion segments using a human cadaveric model to establish factors that are distinguishable and correlated by the location and/or direction of the helical axis throughout motion
Mentor: David Nuckley, PhD

Bora Faulkner, PhD
Project: My research project focuses on understanding the mechanism by which histone deacetylase 4 ( HDAC4 ) regulates osteoclasts gene expression and differentiation. 
Mentor: Kim Mansky, PhD

Sarah Frommer, PhD 
Project: We are investigating the use of stem cells as treatment for Duchenne Muscular Dystrophy.
Mentor: Catherine Verfaillie, MD

Craig Kage
Project: Cervical spine kinematics
Mentor: Arin Ellingson, PhD

Rachel Kahler, PhD 
Project: To define the intentions of the transcription factors, Runx2 and LEF1, and determining the role of LEF1 in osteoblast differentiation.
Mentor: Jennifer Westendorf, PhD

Rebekah Lawrence, PT, DPT, OCS
Project: My primary research aim is to develop a biomechanical model based in kinematic data that will help establish a foundation for a clinical examination of movement impairments for people with shoulder pain. I also plan to attempt to identify the relationships between these biomechanical factors and potential underlying pathoanatomy that may be contributing to the painful condition. We believe this model will result in a more specific diagnostic paradigm from which doctors and physical therapists base their interventions.
Mentor: Paula Ludewig, PhD, PT

Margaret McNulty, PhD 
Project Description: To develop a histological grading scheme for osteoarthritis in mice.
Mentor: Cathy Carlson, DVM, PhD

Branden Moriarity, PhD 
Project: Candidate genes from a forward genetic screen to identify osteosarcoma (OS) development and metastasis genes.
Mentor: David Largaespada, PhD

Christopher Peters, PhD 
Project: Unique cellular interactions that occur within the bone microenvironment in both osteolytic and osteoblastic models of bone cancer.
Mentor: Patrick Mantyh, PhD, JD

Jerid Robinson, PhD 
Project: The natriuretic peptide receptor B (NPR-B), which has relevance in musculoskeletal research via its effects on long bone growth. 
Mentor: Lincoln Potter, PhD

Brandon Smeester
Project Description: My research is focused on the validation of candidate cancer genes using the CRISPR system and testing novel therapuetic targets to treat osteosarcoma.
Mentor(s): Branden Moriarty, PhD and David Largaespada, PhD 

Postdoctoral Alumni

Alexandra Armstrong, DVM
Project: Osteochondrosis (OC)/juvenile osteochondritis dissecans (JOCD)
Mentor: Cathy Carlson, DVM, PhD, DACVP

Randy Daughters, PhD 
Project: Understanding the origin and specification of satellite cells during embryonic development and their contribution to muscle regeneration in Xenopus Laevis tadpole tails.
Mentor: Jonathan Slack, PhD

Dawne Dougherty, PhD 
Project: To understand prostate cancer as it progresses to bone metastases, particularly with respect to the contributing hormonal signaling pathways.
Mentor: Michel Sanders, PhD

Emily Gillespie, MD 
Project: Underlying systemic autoimmune disease with the hope of improving disease management and generating better therapies.
Mentor: Timothy Behrens, MD

Curtis Goreham-Voss, PhD 
Project: Applying finite element analysis to simulate the implant-bone fixation.
Mentor: Joan Bechtold, PhD

Eric Jensen, PhD 
Project: Studying interactions between Runx2 and histone deacetylases in the regulation of bone-specific genes.
Mentor: Jennifer Westendorf, PhD

Kristina Kiefer, DVM 
Project: Evaluating the use of canine adipose derived stem cells as a therapeutic modality for the treatment of intervertebral disc disease and degenerative myelopathy, as well as other various orthopedic conditions in canines.
Mentor: Elizabeth Pluhar, DVM, PhD

Gengyun (Coco) Le, PhD
Project: Advancing the musculoskeletal field by investigating how estrogen affects the inflammatory responses and strength recovery following traumatic muscle injury, and how we can utilize our research to develop therapeutic strategies to prevent, lessen, regain, and finally improve muscle strength in females with low levels of circulating ovarian hormones. I’m also interested in the therapy strategies with bone marrow transplantation and recombinant enzyme modifying behavioral and musculoskeletal impairment in Hurler mice, a mouse model for Hurler Syndrome (or MPS I-H).
Mentor: Dawn Loe, PhD

Amanda Leightner, PhD
Project: To better understand the role of PKD2 in osteoclast differentiation and function. We hypothesize that PKD2 may direct osteoclastogenesis through both control of pre-osteoclast fusion and regulation of the actin cytoskeletal network and podosome dynamics. 
Mentor: Eric Jensen, PhD

Carol Lin, MD 
Project: Compare reoperation rates and outcomes in patients not enrolled or excluded from SPRINT to assess the influence of enrollment in the trial.
Mentor: Marc Swiontkowski, MD

John Looft, PhD
Project Description: Developing a high fidelity shoulder finite element model for clinical applications. The goal of this model is to combine finite element models along with MRI and fluoroscopy to develop predictive models for diagnosing shoulder pain and dysfunction. Additionally working on collaborative research projects improving MRI auto-segmentation software for clinical applications. 
Mentor: Paula Ludewig, PhD

Kai Ludwig, PhD
Project Description: Development and evaluation of advanced magnetic resonance imaging (MRI) techniques at clinical-strength and ultra-high magnetic field for noninvasive diagnosis and monitoring of musculoskeletal (MSK) diseases (e.g. juvenile osteochondritis dissecans (JOCD)). 
Mentor(s):  Jutta Ellermann MD, PhD and Greg Metzger, PhD