YCCMD Pilot Grant Recipients

The entheseal response to Borrelia burgdorferi in murine Lyme borreliosis

Linda K. Bockenstedt, M.D.

Dr. Linda Bockenstedt has a long and distinguished reputation in Lyme disease research. Among other accomplishments, she has developed a novel and accurate microscopic technique to directly assess the critical elements involved in the development of Lyme arthritis lesions. Her proposal will investigate the pathophysiologic basis for Lyme associated enthesitis, particularly with respect to effects on the development of calcium deposits and bony spurs. Further, she will determine whether blockade of certain inflammatory mediators, specifically IL23, known to be involved in the development of tendinitis can attenuate or prevent changes in the tendon and allow the development of targeted therapies aimed at the prevention and treatment of the enthesitis.

Regulation of bone mass homeostasis by the G-protein coupled receptor EB12

Dr. João Pereira is a new faculty recruit who came to Yale from Howard Hughes Medical Institute, UCSF, where he studied the role of the G-protein coupled receptor EBI2 in B cell migration. He has found that that EBI2 is abundantly expressed in monocytes/osteoclast precursors and in bone lining TRAP+ mature osteoclasts. He aims to characterize the role of EBI2 signaling in bone remodeling and to test if Ebi2 directs monocyte/osteoclast migration.

PEDF directs osteoblast differentiation by suppressing PPAR-gamma

Chuhan Chung, M.D.

Dr. Chung joined the faculty at Yale in 2004. He trained in the laboratory of Dr. Susan Crawford at Northwestern University, which focuses on endogenous inhibitors of angiogenesis including PEDF. Dr. Chung has a strong publication record in studies related to PEDF and currently has the PEDF null model in his laboratory. His work at Yale has focused on PEDF related to adiposity and invasive cancer. The recent identification of PEDF as the cause of Osteogenesis Imperfecta type VI has expanded the role of PEDF to bone biology. The phenotypes associated with the metabolic syndrome and OI type VI suggest that PEDF functions at the level of the mesenchymal stem cell. His studies will examine the hypothesis that liver-derived PEDF serves as an endogenous regulator of MSC lineage allocation, and thereby regulating skeletal homeostasis.

Year 15 (April 2013 - March 2014)

Linda K. Bockenstedt, Professor of Medicine, Rheumatology
The entheseal response to Borrelia Burgdorferi in murine Lyme Borreliosis

Chuhan Chung, Associate Professor of Medicine, Digestive Diseases
PEDF directs osteoblast differentiation by suppressing PPARϒ

João P. Pereira, Assistant Professor, Immunobiology
Regulation of bone mass homeostasis by the G-protein coupled receptor EB12

The entheseal response to Borrelia burgdorferi in murine Lyme borreliosis

Dr. Linda Bockenstedt has a long and distinguished reputation in Lyme disease research. Among other accomplishments, she has developed a novel and accurate microscopic technique to directly assess the critical elements involved in the development of Lyme arthritis lesions. Her proposal will investigate the pathophysiologic basis for Lyme associated enthesitis, particularly with respect to effects on the development of calcium deposits and bony spurs. Further, she will determine whether blockade of certain inflammatory mediators, specifically IL23, known to be involved in the development of tendinitis can attenuate or prevent changes in the tendon and allow the development of targeted therapies aimed at the prevention and treatment of the enthesitis.

RELEVANCE TO MUSCULOSKELETAL DISEASES

The Lyme disease spirochete Borrelia burgdorferi causes inflammation in the joints and tendons of people who contract the infection and symptoms at these sites can persist after antibiotic therapy. Our studies in mice have shown that remnants of the spirochete can be retained in the tendons, particularly close to the attachment to bone. This study will define the precise location of the remnants in the tendon insertion into bone and the effects of these remnants on the structural composition of the tendon, particularly with respect to effects on the development of calcium deposits and bony spurs. In addition, we will determine whether blockade of certain inflammatory mediators known to be involved in the development of tendinitis can attenuate or prevent changes in the tendon due to Lyme disease.

Regulation of bone mass homeostasis by the G-protein coupled receptor EB12

Dr. João Pereira is a new faculty recruit who came to Yale from Howard Hughes Medical Institute, UCSF, where he studied the role of the G-protein coupled receptor EBI2 in B cell migration. He has found that that EBI2 is abundantly expressed in monocytes/osteoclast precursors and in bone lining TRAP+ mature osteoclasts. He aims to characterize the role of EBI2 signaling in bone remodeling and to test if Ebi2 directs monocyte/osteoclast migration.

RELEVANCE TO MUSCULOSKELETAL DISEASES

It is estimated that in 2010 approximately 50 million people aged 50 and older in the United States suffer from skeletal diseases caused by low bone mass, such as osteoporosis. Most human skeletal diseases are caused by increased osteoclast activity. Yet, how osteoclasts become attracted to bone remains undefined. Cell migration is largely controlled by GPCRs. Importantly, approximately 30% of all drugs currently on the market modulate GPCR activity. Thus, uncovering the GPCRs guiding osteoclast migration may have a tremendous translational impact.

PEDF directs osteoblast differentiation by suppressing PPAR-gamma

Dr. Chuhan Chung has a strong publication record in studies related to PEDF and currently has the PEDF null model in his laboratory. His work at Yale has focused on PEDF related to adiposity and invasive cancer. The recent identification of PEDF as the cause of Osteogenesis Imperfecta type VI has expanded the role of PEDF to bone biology. THe phenotypes associated with the metabolic syndrome and OI type VI suggest that PEDF functions at the level of the mesenchymal stem cell. Dr. Chung's studies will examine the hypothesis that liver-derived PEDF serves as an endogenous regulator MSC lineage allocation, and therby regulating skeletal homeostasis.

RELEVANCE TO MUSCULOSKELETAL DISEASES

The complete absence of pigment epithelium-derived factor (PEDF) results in Osteogenesis Imperfecta (OI) type VI, a rare bone disease characterized by low mineral content and fractures at an early age. Our research has previously identified that absence of PEDF in mice results in increased fat in several organ systems. Thus, disturbances in PEDF levels are associated with abnormal bone and fat development. To understand these conditions, we are testing PEDF's ability to alter pathways that dictate bone differentiation. In fact, our early data finds that PEDF can induce bone cells while inhibiting fat cells from a common progenitor cell called the mesenchymal stem cell. These findings have clinical relevance to a variety of skeletal diseases such as osteoarthritis and OI type VI.

Year 14 (April 2012 - March 2013)

Michael Centrella, Ph.D., Professor of Surgery (Plastic): Translational control in osteoblasts with relation to C/EBP-delta and IGF-I
Scott Weatherbee, Ph.D., Assistant Professor of Genetics: Mouse Model of Chondrodysplasia
João P. Pereira, Ph.D., Assistant Professor, Immunobiology: Regulation of bone mass homeostasis by the G-protein coupled receptor EB12

Year 13 (April 2011 - March 2012)

Joseph A. Madri, Professor, Pathology & Molecular, Cellular, and Developmental Biology: PECAM-1 polymorphism and osteoclast modulation in osteoporosis
In-Hyun Park, Assistant Professor, Genetics: The role of maintenance DNA methyltransferase (Dnmt1) in muscle development and regeneration

Year 12 (April 2010 - March 2011)

Carolyn Macica, Ph.D., Assistant Professor of Medicine, Endocrinology: The osteoarthropathy of X-linked Hypophosphatemia
Joshua N. Van Houten, Ph.D., Research Scientist, Internal Medicine, Endocrinology: PMCA2 in skeletal metastatic disease in breast cancer
Gerald Shadel, Ph.D., Professor of Pathology: Mouse model of ataxia-telangectasia 

Year 11 (April 2009 - March 2010)

Marie E. Egan, MD, Associate Professor of Pediatrics: Etiology of cystic fibrosis in bone disease
WU, Dianqing, PhD, Professor of Pharmacology: Investigation of the role of ANP-activated protein kinase alpha2 (AMPKa2) in bone homeostasis

Year 10 (April 2008 - March 2009)

Anton Bennett, Professor of Pharmacology: Musculoskeletal Development by a Protein Tyrosine Phosphatase through FGF Receptor Docking Protein
Richard Flavell, Professor of Medicine, Immunology: Regulation of the osteoclastogenesis by IL-1 receptor and Toll-like receptor signaling

Year 9 (April 2007 - March 2008)

Xuesong Chen, PhD, Associate Research Scientist, Internal Medicine Endocrinology: Conditional deletion of PTHrP in articular chondrocytes
Martin Garcia-Castro, PhD, Assistant Professor, Molecular, Cellular & Developmental Biology 

Year 8 (April 2006 - March 2007)

Angela Bruzzaniti, PhD, Associate Research Scientist, Orthopaedics: Characterization of the mechanism by which dynamin regulates osteoclast function
William Philbrick, PhD, Senior Research Scientist, Internal Medicine, Endocrinology: Development of an assay to screen for potential regulators of PTH gene 

Year 7 (April 2005 - March 2006)

Veraragavan Eswarakumar, PhD, Associate Research Scientist, Pharmacology: Investigating the roles of fibroblast growth factors (FGFRs) signaling in membranous and endochondral bone development
Melissa A. Kacena, PhD, Associate Research Scientist, Orthopaedics & Rehabilitation: Regulation of osteoclastogenesis by megakaryocytes
Gunter Wagner, PhD, Professor of Ecology/Evolutionary Biology: Gene chip analysis of limb deformities in frogs

Year 6 (April 2004 - March 2005)

Urszula Masiukiewicz, MD, Assistant Professor of Medicine, Endocrinology: An animal model for low-protein diet induced bone loss

Year 5 (April 2003 - March 2004)

Scott A. Holley, PhD, Assistant Professor of Molecular, Cellular & Developmental Biology: Expression profiling of the zebrafish somitic mesoderm
Archana Sanjay, PhD, Associate Research Scientist, Orthopaedics & Rehabilitation
Steven S. Segal, PhD, Professsor of Cellular and Molecular Physiology / JB Pierce Laboratory: Regenerative neurovascular interactions in muscle

Year 4 (April 2002 - March 2003)

Alfred Bothwell, PhD, Professor of Immunology: Characterization of osteoclast development in Pax5 deficient mice
Frederick Naftolin, MD, Professor of Obstetrics & Gynecology: The effect of the aromatase inhibitor, methyl-testosterone on testosterone-induced bone-sparing
Agnes Vignery, DDS/PhD, Orthopaedics: Role of Mitf and c-Fos in osteoclastogenesis

Year 3 (April 2001 - March 2002)

Arthur E. Broadus, MD/PhD, Professor of Medicine, Endocrinology: Concerning the role of PTHrP in mediating the effects of mechanical force in bone
Chingua Ji, MD/PhD, Department of Surgery, Plastic: TGF-Beta3 and TGF-Beta3 Deficiency
Frank Slack, PhD, Assistant Professor of Molecular, Cellular & Developmental Biology: Role of Murine Lin-41 and Let-7 Genes in limb development
John J. Wysolmerski, MD, Associate Professor of Medicine, Endocrinology: The function of parathyroid hormone-related protein during lactation

Year 2 (April 2000 - March 2001)

Thomas O. Carpenter, MD, Associate Professor of Pediatrics, Endocrinology: Localization of PHEX in living cells with green fluorescent protein
Dinna N. Cruz, MD, Assistant Professor of Medicine, Nephrology: Mutations in the Na-C1 co-transporter and their effects on bone metabolism
Scott W. Wolfe, MD, Professor and Joseph Slade, MD, Assistant Professor of Orthopaedics & Rehabilitation: The relationship of articular cartilage impaction injury and articular surface stepoff to the development of degenerative arthritis in an in vivo intraarticular fracture rabbit model

Year 1 (April 1999 - March 2000)

Thomas O. Carpenter, MD, Associate Professor of Pediatrics, Endocrinology: Localization of PHEX in living cells with green fluorescent protein
William Horn, PhD, Orthopaedics & Rehabilitation: Molecular mechanisms of calcitonin-related signal transduction
Gang-Qing Yao, MD, Associate Research Scientist, Department of Medicine, Comparative Medicine: The effects of soluble and cell-surface forms of CSF-1 on c-fms activation in osteoclasts