The overall goal of this Program Project Application is to improve our understanding of the genetic and molecular control of bone remodeling in the context of aging by identifying a novel regulator, elucidating its modes of action and documenting its clinical importance. The four projects will examine (1) the role of brain-derived serotonin in the regulation of bone formation and its mechanisms of action (Karsenty);(2) the molecular mechanisms whereby gut-derived serotonin regulates osteoblast proliferation and bone formation (Kousteni);(3) the functional hierarchy between brain-derived and gut-derived serotonin as well as the therapeutic potential of inhibiting the synthesis of gut-derived serotonin;(4) the involvement of serotonin in depression-induced and gonadal-failure-induced osteoporosis in humans (Bilezikian). These projects will be supported by two essential cores. Core A is an administrative core integrating a biostatistical support, core B is a Bone Morphometry Core providing histomorphometry and microCT analyses. The coordination of the projects will be performed by the program director. This will be facilitated by the synergy and complementary between the projects, by our monthly meetings, by our interaction with the internal (monthly) and external (yearly) scientific advisory boards and by the supporting roles played by the cores. Together our studies should provide important and novel insights in the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG032959-05
Application #
8728714
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (O3))
Program Officer
Williams, John
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$1,321,402
Indirect Cost
$500,656
Name
Columbia University
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Kode, A; Mosialou, I; Manavalan, S J et al. (2016) FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30:1-13
Karsenty, Gerard; Olson, Eric N (2016) Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell 164:1248-56
Shimazu, Junko; Wei, Jianwen; Karsenty, Gerard (2016) Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148. Cell Rep 15:27-35
Mera, Paula; Laue, Kathrin; Ferron, Mathieu et al. (2016) Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. Cell Metab 23:1078-92
Ortuño, María José; Robinson, Samuel T; Subramanyam, Prakash et al. (2016) Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect. Nat Med 22:1170-1179
Mera, Paula; Laue, Kathrin; Wei, Jianwen et al. (2016) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5:1042-7
Galán-Díez, Marta; Isa, Adiba; Ponzetti, Marco et al. (2016) Normal hematopoiesis and lack of β-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations. Biochim Biophys Acta 1863:490-8
Makinistoglu, Munevver Parla; Karsenty, Gerard (2015) The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts. Mol Metab 4:64-9
Wei, Jianwen; Karsenty, Gerard (2015) An overview of the metabolic functions of osteocalcin. Rev Endocr Metab Disord 16:93-8
Kode, Aruna; Manavalan, John S; Mosialou, Ioanna et al. (2014) Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506:240-4

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