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Grant Details

Grant Number: 5R01CA163640-05 Interpret this number
Primary Investigator: Cao, Lei
Organization: Ohio State University
Project Title: Identifying Brain Mediators Distinguishing Eustress and Distress Impact on Cancer
Fiscal Year: 2017
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Abstract

DESCRIPTION (provided by applicant): Cancer is influenced by an individual's interaction with its physical and social environment, yet the underlying mechanisms are poorly defined. Epidemiological studies have revealed that social support is linked to improved health outcomes among cancer patients whereas social isolation predicts risk for mortality. Mechanistic studies in chronic stress models suggest that prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal medullary (SAM) axis may promote cancer progression. Our recent work has shown that environmental enrichment (EE), a housing environment boosting mental health, inhibits tumor growth by activating the hypothalamic- sympathoneural-adipocyte (HSA) axis. The stimulations provided in EE stimulate brain- derived neurotrophic factor (BDNF) expression in the hypothalamus leading to preferential sympathoneural activation of white fat. The elevated sympathetic drive activates adipocyte -adrenergic receptors inhibiting leptin expression and release, and thereby suppresses cancer growth. In contrast, social isolation (SI) is linked to increased tumor burden. However, both EE and SI increase the classical stress hormones, glucocorticoids and catecholamines, and -adrenergic blockers may abrogate their effects on cancer. This apparent paradox may in part lie in the lack of recognition of the difference between "eustress" (positive stress) and "distress" (negative stress) and their opposing health outcomes. The long-term goal of this project is to understand how the eustressful and distressful events trigger distinct molecular changes in the brain leading to an orchestrated differential activation of the three neuroendocrine axes: HPA, SAM and HSA, and subsequent opposite influences on cancer. Specifically we propose to use a multidisciplinary approach to provide a comprehensive and explicit comparison between the eustress model EE versus distress model SI on cancer progression, metabolism, and fat physiology. The analysis of the nature and magnitude of the 3 axes will help to elucidate the mechanisms underlying eustress-associated anticancer versus distress-associated pro- cancer phenotype. In addition we plan to profile the gene expression in the laser-capture microdissected hypothalamus nuclei to identify molecular mediators distinguishing eustress and distress. Furthermore we will investigate the role of hypothalamic BDNF in mediating SI impact on cancer. These studies may reveal novel therapeutic targets for cancer prevention and treatment.

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Publications

Insulin Modulates Excitatory Synaptic Transmission and Synaptic Plasticity in the Mouse Hippocampus.
Authors: Zhao F. , Siu J.J. , Huang W. , Askwith C. , Cao L. .
Source: Neuroscience, 2019-07-15; 411, p. 237-254.
EPub date: 2019-05-28.
PMID: 31146008
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Adipocytes: A Novel Target for IL-15/IL-15R? Cancer Gene Therapy.
Authors: Xiao R. , Mansour A.G. , Huang W. , Chrislip L.A. , Wilkins R.K. , Queen N.J. , Youssef Y. , Mao H.C. , Caligiuri M.A. , Cao L. .
Source: Molecular therapy : the journal of the American Society of Gene Therapy, 2019-05-08; 27(5), p. 922-932.
EPub date: 2019-02-16.
PMID: 30833178
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Long-term environmental enrichment affects microglial morphology in middle age mice.
Authors: Ali S. , Liu X. , Queen N.J. , Patel R.S. , Wilkins R.K. , Mo X. , Cao L. .
Source: Aging, 2019-04-29; 11(8), p. 2388-2402.
PMID: 31039130
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Hypothalamic gene transfer of BDNF promotes healthy aging in mice.
Authors: McMurphy T. , Huang W. , Liu X. , Siu J.J. , Queen N.J. , Xiao R. , Cao L. .
Source: Aging cell, 2019 Apr; 18(2), p. e12846.
EPub date: 2018-12-26.
PMID: 30585393
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Enriched environment inhibits breast cancer progression in obese models with intact leptin signaling.
Authors: Foglesong G. , Queen N. , Huang W. , Widstrom K. , Cao L. .
Source: Endocrine-related cancer, 2019-03-01; , .
EPub date: 2019-03-01.
PMID: 30856610
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Enriched environment regulates thymocyte development and alleviates experimental autoimmune encephalomyelitis in mice.
Authors: Xiao R. , Bergin S.M. , Huang W. , Mansour A.G. , Liu X. , Judd R.T. , Widstrom K.J. , Queen N.J. , Wilkins R.K. , Siu J.J. , et al. .
Source: Brain, behavior, and immunity, 2019 Jan; 75, p. 137-148.
EPub date: 2018-10-01.
PMID: 30287389
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Implementation of environmental enrichment after middle age promotes healthy aging.
Authors: McMurphy T. , Huang W. , Queen N.J. , Ali S. , Widstrom K.J. , Liu X. , Xiao R. , Siu J.J. , Cao L. .
Source: Aging, 2018-07-20; 10(7), p. 1698-1721.
PMID: 30036185
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Molecular Therapy of Melanocortin-4-Receptor Obesity by an Autoregulatory BDNF Vector.
Authors: Siu J.J. , Queen N.J. , Liu X. , Huang W. , McMurphy T. , Cao L. .
Source: Molecular therapy. Methods & clinical development, 2017-12-15; 7, p. 83-95.
EPub date: 2017-09-29.
PMID: 29296625
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Induction of adipose and hepatic SWELL1 expression is required for maintaining systemic insulin-sensitivity in obesity.
Authors: Xie L. , Zhang Y. , Gunasekar S.K. , Mishra A. , Cao L. , Sah R. .
Source: Channels (Austin, Tex.), 2017-11-02; 11(6), p. 673-677.
EPub date: 2017-10-05.
PMID: 28873008
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Targeting Visceral Fat by Intraperitoneal Delivery of Novel AAV Serotype Vector Restricting Off-Target Transduction in Liver.
Authors: Huang W. , Liu X. , Queen N.J. , Cao L. .
Source: Molecular therapy. Methods & clinical development, 2017-09-15; 6, p. 68-78.
EPub date: 2017-06-19.
PMID: 28702474
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An Obesity Paradox: Increased Body Mass Index Is Associated with Decreased Aortic Atherosclerosis.
Authors: Barth R.F. , Maximilian Buja L. , Cao L. , Brodsky S.V. .
Source: Current hypertension reports, 2017 Jul; 19(7), p. 55.
PMID: 28593612
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miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice.
Authors: Ng R. , Hussain N.A. , Zhang Q. , Chang C. , Li H. , Fu Y. , Cao L. , Han W. , Stunkel W. , Xu F. .
Source: Cell reports, 2017-05-09; 19(6), p. 1229-1246.
PMID: 28494871
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Improved gene delivery to adult mouse spinal cord through the use of engineered hybrid adeno-associated viral serotypes.
Authors: Siu J.J. , Queen N.J. , Huang W. , Yin F.Q. , Liu X. , Wang C. , McTigue D.M. , Cao L. .
Source: Gene therapy, 2017 06; 24(6), p. 361-369.
EPub date: 2017-04-25.
PMID: 28440798
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SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis.
Authors: Zhang Y. , Xie L. , Gunasekar S.K. , Tong D. , Mishra A. , Gibson W.J. , Wang C. , Fidler T. , Marthaler B. , Klingelhutz A. , et al. .
Source: Nature cell biology, 2017 05; 19(5), p. 504-517.
EPub date: 2017-04-24.
PMID: 28436964
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Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals.
Authors: Zhu Y. , Gao Y. , Tao C. , Shao M. , Zhao S. , Huang W. , Yao T. , Johnson J.A. , Liu T. , Cypess A.M. , et al. .
Source: Cell metabolism, 2016-09-13; 24(3), p. 420-433.
PMID: 27626200
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Anticancer Molecules in Brain: Implication for Novel Strategy for Cancer Immunotherapy.
Authors: Xiao R. , Bergin S.M. , Zhang M. , Cao L. .
Source: Immunotherapy (Los Angeles, Calif.), 2016 Sep; 2(3), .
EPub date: 2016-07-11.
PMID: 28299372
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Hepatic Expression of Adenovirus 36 E4ORF1 Improves Glycemic Control and Promotes Glucose Metabolism Through AKT Activation.
Authors: McMurphy T.B. , Huang W. , Xiao R. , Liu X. , Dhurandhar N.V. , Cao L. .
Source: Diabetes, 2017 02; 66(2), p. 358-371.
EPub date: 2016-11-30.
PMID: 27903748
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Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype.
Authors: Xiao R. , Bergin S.M. , Huang W. , Slater A.M. , Liu X. , Judd R.T. , Lin E.D. , Widstrom K.J. , Scoville S.D. , Yu J. , et al. .
Source: Cancer immunology research, 2016 06; 4(6), p. 488-497.
EPub date: 2016-04-04.
PMID: 27045020
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Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector.
Authors: Huang W. , McMurphy T. , Liu X. , Wang C. , Cao L. .
Source: Molecular therapy : the journal of the American Society of Gene Therapy, 2016 06; 24(6), p. 1062-1069.
EPub date: 2016-02-09.
PMID: 26857843
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Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice.
Authors: Foglesong G.D. , Huang W. , Liu X. , Slater A.M. , Siu J. , Yildiz V. , Salton S.R. , Cao L. .
Source: Endocrinology, 2016 Mar; 157(3), p. 983-96.
EPub date: 2016-01-05.
PMID: 26730934
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A Protocol for Housing Mice in an Enriched Environment.
Authors: Slater A.M. , Cao L. .
Source: Journal of visualized experiments : JoVE, 2015-06-08; (100), p. e52874.
EPub date: 2015-06-08.
PMID: 26131694
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Adipose VEGF Links the White-to-Brown Fat Switch With Environmental, Genetic, and Pharmacological Stimuli in Male Mice.
Authors: During M.J. , Liu X. , Huang W. , Magee D. , Slater A. , McMurphy T. , Wang C. , Cao L. .
Source: Endocrinology, 2015 Jun; 156(6), p. 2059-73.
EPub date: 2015-03-12.
PMID: 25763639
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Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice.
Authors: Liu X. , McMurphy T. , Xiao R. , Slater A. , Huang W. , Cao L. .
Source: Molecular therapy : the journal of the American Society of Gene Therapy, 2014 Jul; 22(7), p. 1275-1284.
EPub date: 2014-03-18.
PMID: 24637454
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Adipose tissue insulin receptor knockdown via a new primate-derived hybrid recombinant AAV serotype.
Authors: Liu X. , Magee D. , Wang C. , McMurphy T. , Slater A. , During M. , Cao L. .
Source: Molecular therapy. Methods & clinical development, 2014-02-05; 1, .
PMID: 25383359
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The anti-tumor activity of a neutralizing nanobody targeting leptin receptor in a mouse model of melanoma.
Authors: McMurphy T. , Xiao R. , Magee D. , Slater A. , Zabeau L. , Tavernier J. , Cao L. .
Source: PloS one, 2014; 9(2), p. e89895.
EPub date: 2014-02-28.
PMID: 24587106
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