Grant Details
Grant Number: |
1R01CA163640-01A1 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: |
2013 |
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 ss-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 ss-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.
Publications
Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.
Authors: Anderson J.M.
, Arnold W.D.
, Huang W.
, Ray A.
, Owendoff G.
, Cao L.
.
Source: Gene Therapy, 2023-09-12 00:00:00.0; , .
EPub date: 2023-09-12 00:00:00.0.
PMID: 37699965
Related Citations
Protocol to minimize the confounding effect of cold stress on socially isolated mice using thermoneutral housing.
Authors: Appana B.
, Queen N.J.
, Cao L.
.
Source: Star Protocols, 2023-09-02 00:00:00.0; 4(3), p. 102533.
EPub date: 2023-09-02 00:00:00.0.
PMID: 37660300
Related Citations
Environmental Enrichment Improves Motor Function and Muscle Transcriptome of Aged Mice.
Authors: Huang W.
, Bates R.
, Zou X.
, Queen N.J.
, Mo X.
, Arnold W.D.
, Ray A.
, Owendoff G.
, Cao L.
.
Source: Advanced Biology, 2023-07-30 00:00:00.0; , p. e2300148.
EPub date: 2023-07-30 00:00:00.0.
PMID: 37518850
Related Citations
Social isolation exacerbates diet-induced obesity and peripheral inflammation in young male mice under thermoneutrality.
Authors: Queen N.J.
, Huang W.
, Komatineni S.
, Mansour A.G.
, Xiao R.
, Chrislip L.A.
, Cao L.
.
Source: Iscience, 2023-03-17 00:00:00.0; 26(3), p. 106259.
EPub date: 2023-02-21 00:00:00.0.
PMID: 36915694
Related Citations
Adipocyte CD1d Gene Transfer Induces T Cell Expansion and Adipocyte Inflammation in CD1d Knockout Mice.
Authors: Xiao R.
, Mansour A.G.
, Huang W.
, Hassan Q.N.
, Wilkins R.K.
, Komatineni S.V.
, Bates R.
, Ali S.
, Chrislip L.A.
, Queen N.J.
, et al.
.
Source: Journal Of Immunology (baltimore, Md. : 1950), 2022-05-01 00:00:00.0; 208(9), p. 2109-2121.
EPub date: 2022-04-13 00:00:00.0.
PMID: 35418470
Related Citations
eNAMPT actions through nucleus accumbens NAD+/SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress.
Authors: Morató L.
, Astori S.
, Zalachoras I.
, Rodrigues J.
, Ghosal S.
, Huang W.
, Guillot de Suduiraut I.
, Grosse J.
, Zanoletti O.
, Cao L.
, et al.
.
Source: Science Advances, 2022-03-04 00:00:00.0; 8(9), p. eabj9109.
EPub date: 2022-03-02 00:00:00.0.
PMID: 35235362
Related Citations
Environmental Enrichment Mitigates Age-Related Metabolic Decline and Lewis Lung Carcinoma Growth in Aged Female Mice.
Authors: Queen N.J.
, Deng H.
, Huang W.
, Mo X.
, Wilkins R.K.
, Zhu T.
, Wu X.
, Cao L.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2021 Dec; 14(12), p. 1075-1088.
EPub date: 2021-09-17 00:00:00.0.
PMID: 34535449
Related Citations
Environmental activation of a hypothalamic BDNF-adipocyte IL-15 axis regulates adipose-natural killer cells.
Authors: Bergin S.M.
, Xiao R.
, Huang W.
, Judd C.R.T.
, Liu X.
, Mansour A.G.
, Queen N.
, Widstrom K.J.
, Caligiuri M.A.
, Cao L.
.
Source: Brain, Behavior, And Immunity, 2021 07; 95, p. 477-488.
EPub date: 2021-05-12 00:00:00.0.
PMID: 33989745
Related Citations
LMO3 reprograms visceral adipocyte metabolism during obesity.
Authors: Wagner G.
, Fenzl A.
, Lindroos-Christensen J.
, Einwallner E.
, Husa J.
, Witzeneder N.
, Rauscher S.
, Gröger M.
, Derdak S.
, Mohr T.
, et al.
.
Source: Journal Of Molecular Medicine (berlin, Germany), 2021-05-20 00:00:00.0; , .
EPub date: 2021-05-20 00:00:00.0.
PMID: 34018016
Related Citations
Visceral adipose tissue-directed FGF21 gene therapy improves metabolic and immune health in BTBR mice.
Authors: Queen N.J.
, Bates R.
, Huang W.
, Xiao R.
, Appana B.
, Cao L.
.
Source: Molecular Therapy. Methods & Clinical Development, 2021-03-12 00:00:00.0; 20, p. 409-422.
EPub date: 2020-12-25 00:00:00.0.
PMID: 33575433
Related Citations
Hypothalamic gene transfer of BDNF promotes healthy aging.
Authors: Cao L.
, Ali S.
, Queen N.J.
.
Source: Vitamins And Hormones, 2021; 115, p. 39-66.
EPub date: 2021-01-30 00:00:00.0.
PMID: 33706955
Related Citations
Adipose Tissue: An Emerging Target for Adeno-associated Viral Vectors.
Authors: Bates R.
, Huang W.
, Cao L.
.
Source: Molecular Therapy. Methods & Clinical Development, 2020-12-11 00:00:00.0; 19, p. 236-249.
EPub date: 2020-09-20 00:00:00.0.
PMID: 33102616
Related Citations
Enriched environment enhances NK cell maturation through hypothalamic BDNF in male mice.
Authors: Mansour A.G.
, Xiao R.
, Bergin S.M.
, Huang W.
, Chrislip L.A.
, Zhang J.
, Ali S.
, Queen N.J.
, Caligiuri M.A.
, Cao L.
.
Source: European Journal Of Immunology, 2020-11-10 00:00:00.0; , .
EPub date: 2020-11-10 00:00:00.0.
PMID: 33169371
Related Citations
Adipose PTEN acts as a downstream mediator of a brain-fat axis in environmental enrichment.
Authors: Huang W.
, Queen N.J.
, McMurphy T.B.
, Ali S.
, Wilkins R.K.
, Appana B.
, Cao L.
.
Source: Comprehensive Psychoneuroendocrinology, 2020 Nov; 4, .
EPub date: 2020-11-02 00:00:00.0.
PMID: 35355831
Related Citations
Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis.
Authors: Hassan Q.N.
, Queen N.J.
, Cao L.
.
Source: Translational Cancer Research, 2020 Sep; 9(9), p. 5687-5699.
PMID: 33134111
Related Citations
CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.
Authors: Ali S.
, Mansour A.G.
, Huang W.
, Queen N.J.
, Mo X.
, Anderson J.M.
, Hassan Ii Q.N.
, Patel R.S.
, Wilkins R.K.
, Caligiuri M.A.
, et al.
.
Source: Aging, 2020-02-02 00:00:00.0; 12(3), p. 2101-2122.
EPub date: 2020-02-02 00:00:00.0.
PMID: 32007953
Related Citations
Environmental enrichment improves metabolic and behavioral health in the BTBR mouse model of autism.
Authors: Queen N.J.
, Boardman A.A.
, Patel R.S.
, Siu J.J.
, Mo X.
, Cao L.
.
Source: Psychoneuroendocrinology, 2020 Jan; 111, p. 104476.
EPub date: 2019-10-15 00:00:00.0.
PMID: 31648110
Related Citations
Improvements to Healthspan Through Environmental Enrichment and Lifestyle Interventions: Where Are We Now?
Authors: Queen N.J.
, Hassan Q.N.
, Cao L.
.
Source: Frontiers In Neuroscience, 2020; 14, p. 605.
EPub date: 2020-06-12 00:00:00.0.
PMID: 32655354
Related Citations
Adipose PTEN regulates adult adipose tissue homeostasis and redistribution via a PTEN-leptin-sympathetic loop.
Authors: Huang W.
, Queen N.J.
, McMurphy T.B.
, Ali S.
, Cao L.
.
Source: Molecular Metabolism, 2019 12; 30, p. 48-60.
EPub date: 2019-09-28 00:00:00.0.
PMID: 31767180
Related Citations
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 00:00:00.0; 411, p. 237-254.
EPub date: 2019-05-28 00:00:00.0.
PMID: 31146008
Related Citations
Adipocytes: A Novel Target for IL-15/IL-15Rα 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 00:00:00.0; 27(5), p. 922-932.
EPub date: 2019-02-16 00:00:00.0.
PMID: 30833178
Related Citations
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 00:00:00.0; 11(8), p. 2388-2402.
PMID: 31039130
Related Citations
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 00:00:00.0.
PMID: 30585393
Related Citations
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 00:00:00.0; , .
EPub date: 2019-03-01 00:00:00.0.
PMID: 30856610
Related Citations
rAAV-Mediated Gene Delivery to Adipose Tissue.
Authors: Huang W.
, Queen N.J.
, Cao L.
.
Source: Methods In Molecular Biology (clifton, N.j.), 2019; 1950, p. 389-405.
PMID: 30783987
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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, 2018-10-01 00:00:00.0; , .
EPub date: 2018-10-01 00:00:00.0.
PMID: 30287389
Related Citations
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 00:00:00.0; 10(7), p. 1698-1721.
PMID: 30036185
Related Citations
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 00:00:00.0; 7, p. 83-95.
EPub date: 2017-09-29 00:00:00.0.
PMID: 29296625
Related Citations
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 00:00:00.0; 11(6), p. 673-677.
EPub date: 2017-10-05 00:00:00.0.
PMID: 28873008
Related Citations
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 00:00:00.0; 6, p. 68-78.
EPub date: 2017-06-19 00:00:00.0.
PMID: 28702474
Related Citations
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
Related Citations
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 00:00:00.0; 19(6), p. 1229-1246.
PMID: 28494871
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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 00:00:00.0.
PMID: 28436964
Related Citations
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, 2017-04-25 00:00:00.0; , .
PMID: 28440798
Related Citations
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 Feb; 66(2), p. 358-371.
PMID: 27903748
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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 00:00:00.0; 24(3), p. 420-33.
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), .
PMID: 28299372
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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 Jun; 24(6), p. 1062-9.
PMID: 26857843
Related Citations
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.J.
, Widstrom K.J.
, Scoville S.D.
, Yu J.
, et al.
.
Source: Cancer Immunology Research, 2016 06; 4(6), p. 488-97.
PMID: 27045020
Related Citations
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.
PMID: 26730934
Related Citations
A Protocol for Housing Mice in an Enriched Environment.
Authors: Slater A.M.
, Cao L.
.
Source: Journal Of Visualized Experiments : Jove, 2015-06-08 00:00:00.0; (100), p. e52874.
EPub date: 2015-06-08 00:00:00.0.
PMID: 26131694
Related Citations
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.
PMID: 25763639
Related Citations
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. 1275-84.
PMID: 24637454
Related Citations
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 00:00:00.0; 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.
PMID: 24587106
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