Capitalizing on 15 years of research in multiple laboratories in this area the goal of this Program Project application is to provide a comprehensive and mechanistic understanding of the cross-talk existing between bone and the brain by addressing four issues. First, the discovery that brain-derived serotonin favors bone mass accrual by inhibiting the activity of the sympathetic nervous system raises questions about the transcriptional mechanisms regulating brain serotonin accumulation and catecholamine synthesis. Second, the role played by factors coming from the mothers in the offspring brain development and cognition raises the question that a similar influence for bone mass acquisition may exist. Third, that Tph1, the initial enzyme in the synthesis of gut-derived serotonin is also needed for melatonin synthesis in pineal gland raises the question of the possible role of melatonin as a regulator of bone mass accrual. Our hypothesis is that one extracellular cue limiting the influence of the sympathetic tone on osteoblast functions could be melatonin. Fourth, if we now look at the relationship between bone and the brain from the point of view of bone, the powerful but inhibitory regulation of bone mass accrual by the brain raises the question of whether bone limits this deleterious influence by acting directly in the brain. In addressing these fundamental questions of bone biology and whole-organism physiology the laboratories of the three project leaders of this application have generated in the last five years enough preliminary data to justify their respective projects. The three major questions tackled by this Program Project are: * To determine the influences of bone remodeling via osteocalcin on the metabolic status and cognition of mice as they age. * To demonstrate that one mechanism by which the longevity-associated protein Sirtuin 1 regulates bone mass is through its functions in the brain. * To define the role of melatonin in bone remodeling during growth, aging and gonadal failure and determine whether maternal by-products of Tph1 are determinants of peak bone mass and future bone health of the offspring.

Public Health Relevance

The goal of this Program Project application is 1) to elucidate the molecular bases of the regulation of bone mass by neurotransmitters by studying neurons producing them and osteoblasts responding to them, 2) to determine the influence of the bone-derived hormone osteocalcin on the status of energy metabolism and cognition during aging and 3) to further explore maternal influences on cognition and peak bone mass in the offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG032959-10
Application #
9694567
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Williams, John
Project Start
2010-08-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
De Vadder, Filipe; Grasset, Estelle; MannerĂ¥s Holm, Louise et al. (2018) Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci U S A 115:6458-6463
Obri, Arnaud; Khrimian, Lori; Karsenty, Gerard et al. (2018) Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol 14:174-182
Khrimian, Lori; Obri, Arnaud; Karsenty, Gerard (2017) Modulation of cognition and anxiety-like behavior by bone remodeling. Mol Metab 6:1610-1615
Khrimian, Lori; Obri, Arnaud; Ramos-Brossier, Mariana et al. (2017) Gpr158 mediates osteocalcin's regulation of cognition. J Exp Med 214:2859-2873
Mosialou, Ioanna; Shikhel, Steven; Liu, Jian-Min et al. (2017) MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543:385-390
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
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 23:1078-1092
Karsenty, Gerard; Olson, Eric N (2016) Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell 164:1248-1256
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

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