Since graduating college 14years ago, I have committed myself to a career in academic biomedical research. As a PhD student at New York University in the 1990s, I worked on innate immune responses to oacterial pathogens. After completing medical school with high honors in 2001, I trained in both Internal Medicine and Rheumatology. Two years ago, I decided to pursue the post-doctoral phase of my career with Dr. Laurie Glimcher, a world-renowned immunologist and transcription factor biologist. In Dr. Glimcher's lab, I have developed a keen interest in bone resorption by osteoclasts. Dysregulation of osteoclasts contributes to the pathogenesis of musculoskeletal disorders that I see in my weekly rheumatology clinic, such as osteoporosis and inflammatory arthritis. Nuclear Factor of Activated T-cells (NFATs) are a family of transcription factors important for cellular differentiation pathways and have been implicated in osteoclastogenesis. We generated a murine conditional knockout of NFATd using Cre-loxP technology. Deletion of NFATd results in osteopetrosis and a defect in osteoclastogenesis.
In Aim 1, the role of NFATd in osteoclasts is explored under physiologic conditions and in a model of glucocorticoid-induced osteoporosis. We have recently discovered that in the absence of NFATd, osteoclast precursors make osteoprotegerin, a potent inhibitor of osteoclast differentiation.
In Aim 2, the mechanism and consequence of this observation is explored. Lastly, a high throughput screen using RNAi technology has been initiated to identify novel regulators of osteoclast differentiation.
Aim 3 seeks to validate the "hits" identified in the initial screen and generate a list of targets to explore during the impendent phase of my career. Dr. Glimcher's lab and the Harvard University Biomedical community is the ideal setting to pursue these ambitious projects. Expertise in skeletal biology surrounds us and I have established the appropriate mentors and collaborators. These experiments and my career development plan will train me in the techniques needed to direct a laboratory focused on elucidating the mechanisms of osteoclast development and pathologic bone destruction. Osteoporosis is a devastating disease that causes brittle bones and afflicts millions of Americans. The osteoclast is the only cell capable of destroying bone. This grant seeks to define the genes that regulate the development and function of the osteoclast.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR054859-05
Application #
8257980
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Chen, Faye H
Project Start
2008-07-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$130,950
Indirect Cost
$9,700
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Baumgart, Sandra; Chen, Nai-Ming; Siveke, Jens T et al. (2014) Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov 4:688-701
Ritter, Susan Y; Collins, Jamie; Krastins, Bryan et al. (2014) Mass spectrometry assays of plasma biomarkers to predict radiographic progression of knee osteoarthritis. Arthritis Res Ther 16:456
Charles, Julia F; Aliprantis, Antonios O (2014) Osteoclasts: more than 'bone eaters'. Trends Mol Med 20:449-59
Greenblatt, Matthew B; Ritter, Susan Y; Wright, John et al. (2013) NFATc1 and NFATc2 repress spontaneous osteoarthritis. Proc Natl Acad Sci U S A 110:19914-9
Ritter, Susan Y; Subbaiah, Roopashree; Bebek, Gurkan et al. (2013) Proteomic analysis of synovial fluid from the osteoarthritic knee: comparison with transcriptome analyses of joint tissues. Arthritis Rheum 65:981-92
Coury, Fabienne; Zenger, Serhan; Stewart, Andrew K et al. (2013) SLC4A2-mediated Cl-/HCO3- exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts. Proc Natl Acad Sci U S A 110:2163-8
Greenblatt, Matthew B; Aliprantis, Antonios O (2013) The immune pathogenesis of scleroderma: context is everything. Curr Rheumatol Rep 15:297
Greenblatt, Matthew B; Vrbanac, Vladimir; Vbranac, Vladimir et al. (2012) Graft versus host disease in the bone marrow, liver and thymus humanized mouse model. PLoS One 7:e44664
Wein, Marc N; Jones, Dallas C; Shim, Jae-Hyuck et al. (2012) Control of bone resorption in mice by Schnurri-3. Proc Natl Acad Sci U S A 109:8173-8
Greenblatt, Matthew B; Sargent, Jennifer L; Farina, Giuseppina et al. (2012) Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am J Pathol 180:1080-94

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