MECHANISMS OF ACTION OF GHRELIN IN MUSCLE AND ADIPOSE TISSUE IN CANCER-RELATED CA
Jose M Garcia, Assistant Professor
Michael E Debakey Va Medical Center, Houston, Tx 77030-4211
Abstract: 6. Project Summary/ Every year, over 1.5 million individuals in the US are diagnosed with cancer. Cachexia, defined as an involuntary weight loss >5%, is present in up to 80% of these patients and it encompasses the loss of muscle and fat mass. Cachexia also contributes to a decrease in functional performance, quality of life and survival. However, treatments for this condition are lacking. Ghrelin, a novel hormone released primarily by the stomach stimulates GH secretion, increases energy intake and decreases energy expenditure. More recently it has been postulated to have anti-inflammatory actions. In our model of cachexia, administration of ghrelin induced an increase in lean body mass (LBM) and fat mass. However, its mechanisms of action in this setting are not fully understood. The long-term objective of this research is to determine the extent to which ghrelin improves cachexia and to establish the mechanisms mediating ghrelin´s action in muscle and adipose tissue in this setting. Our hypotheses are that in the setting of cancer- and cisplatin-induced cachexia, ghrelin will prevent muscle wasting by downregulating proteolysis through the ubiquitin-proteasome pathway. These changes will be mediated through a) increases in energy intake, b) activation of insulin-like growth factor-1 (IGF-1)-dependent pathways and c) downregulation of nuclear factor kappa B (NFB)-dependent inflammatory pathways. We also hypothesize that ghrelin will prevent fat loss by decreasing lipolysis and by favoring fat storage. These changes will be mediated through a) increasing food intake, b) decreasing energy expenditure and c) downregulating NFB-dependent inflammatory pathways. The specific aims are to 1) Establish the mechanisms mediating ghrelin-induced muscle preservation in the setting of cisplatin-induced cachexia; 2) Determine the mechanisms involved in ghrelin-induced fat deposition in the setting of cisplatin-induced cachexia; and 3) Characterize the effects of ghrelin in a tumor model of cachexia induced by the Lewis lung carcinoma (LLC) cell line. Research Design and Methods In our rodent model of cisplatin-induced cachexia we have observed that ghrelin prevents cisplatin-induced fat and muscle atrophy. We are now proposing to determine the mechanisms involved in this setting and further characterize these pathways by using a different model of cachexia induced by LLC cell line. We will determine the role of endogenous ghrelin and the ghrelin receptor GHSR-1a by setting up our model of cachexia in ghrelin and GHSR1a knock-outs. We will establish the role of NFB and inflammation by exploiting a new transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NFB consensus binding sites. The role of NFB will be confirmed by using NFB antagonists. The extent to which food intake regulates the pathways controlling fat and muscle mass will be established by performing pair-feeding experiments. The relative contribution of GH/IGF-1 activation to ghrelin´s action will be tested by the administration of IGF-1 and GH receptor antagonists. Energy expenditure measurements will be performed by indirect calorimetry. Based on the data generated in our current model, we also will test the hypothesis that the same mechanisms are implicated in the setting of LLC tumor -induced cachexia. Taken together, these experiments will determine the mechanisms mediating ghrelin´s protective effects in the setting of fat and muscle wasting related to cancer, addressing a clinical need and filling a void in the literature. 7. Cancer will affect 1 in 2 veterans and involuntary weight loss (also known as cachexia) resulting from a loss of fat and muscle mass will affect the vast majority of these patients. Cachexia often reduces functionality leading to a decrease in quality of life, poor response to anti-cancer therapies and increased mortality. Currently there is no effective way to treat cachexia. The novel hormone ghrelin increases appetite and body weight. This proposal will determine its effects and mechanisms of action in muscle and fat in the setting of cachexia. The results generated by this proposal will help us to develop treatments for cachexia, improving quality of life. By increasing muscle mass and function, patients will tolerate more effective treatments. They also will be able to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions
Relevance: 7. Cancer will affect 1 in 2 veterans and involuntary weight loss (also known as cachexia) resulting from a loss of fat and muscle mass will affect the vast majority of these patients. Cachexia often reduces functionality leading to a decrease in quality of life, poor response to anti-cancer therapies and increased mortality. Currently there is no effective way to treat cachexia. The novel hormone ghrelin increases appetite and body weight. This proposal will determine its effects and mechanisms of action in muscle and fat in the setting of cachexia. The results generated by this proposal will help us to develop treatments for cachexia, improving quality of life. By increasing muscle mass and function, patients will tolerate more effective treatments. They also will be able to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare. Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions
Project start date: 2009-10-01
Project end date: 2012-09-30
Budget start date: 1-OCT-2009
Budget end date: 30-SEP-2010
PFA/PA: RFA-BX-09-001
1I01BX000507-01 (2009): $0
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Jose M Garcia
THE ROLE OF GHRELIN IN CISPLATIN-INDUCED INFERTILITY
Jose M Garcia
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5R21HD060870-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: More than 50% of male cancer patients subjected to cisplatin-based chemotherapy will suffer from long-term infertility. This is a significant concern because many of these patients are children or young men who survive their cancer and would hope to later reproduce. However, medical treatment for chemotherapy-induced infertility is not currently available. A key factor in the development of cisplatin-induced infertility is germ cell apoptosis, and activation of the proapoptotic mediators p53 and Nuclear Factor kappa B (NF?B) has been implicated in its development. Ghrelin, a novel hormone, has anti-apoptotic properties and suppresses NF?B in other tissues. Our preliminary studies indicate that it reduces cisplatin-induced apoptosis in germ cells. However, ghrelin´s mechanism(s) of action in this setting and its effect on fertility are unknown. The long-term objectives of this application are a) to develop new strategies for preserving fertility in individuals exposed to chemotherapeutic drugs and b) to establish the mechanisms mediating ghrelin´s effects in this setting. Hypothesis We hypothesize that ghrelin will prevent cisplatin-induced infertility and downregulate testicular NF?B and p53 activation induced by cisplatin. Our specific aims are 1) To determine the effect of ghrelin administration on cisplatin-induced infertility and 2) To establish the effects of ghrelin and cisplatin on testicular p53 and NF?B activity. Design and methods In our rodent model of cisplatin-induced gonadal damage we have observed that ghrelin prevents cisplatin-induced testicular apoptosis and NF?B activation. We are now proposing to test the effects of ghrelin and cisplatin on fertility, p53 and NF?B activity by exploiting a new transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NF?B consensus binding sites. Based on the data generated in our adult model, we also will establish the feasibility of a prepubertal model of infertility. Significance Fertility is the major life-style concern in more than 80% of children and men who are long-term survivors of cancer chemotherapy. Establishing the mechanisms and effects of ghrelin on fertility, germ cell apoptosis and NF?B and p53 activity in this setting will be important to develop methods to prevent or reverse the infertility caused by cisplatin and other chemotherapeutic agents. Such a pursuit will have relevance for maintaining long-term fertility in men who are exposed to chemotherapeutic agents, chemicals or radiation. A significant proportion of children and men receiving chemotherapy for the treatment of cancer suffer damage to their reproductive organs leading to infertility. We currently do not have a way to prevent or predict who will become infertile after receiving chemotherapy; however, our preliminary work shows for the first time that a new hormone called "ghrelin" prevents this damage to the reproductive organs due to chemotherapy. The experiments we propose here will determine the effects of ghrelin on fertility and will lead us to the development of new ways to prevent or treat infertility
Keywords: (17Beta)-17-hydroxyandrost-4-en-3-one; (SP-4-2)-Diamminedichloroplatinum; 0-11 years old; 17-beta-Hydroxy-4-Androsten-3-one; 21+ years old; ADRGND; Adipose tissue; Adrenal Glands; Adrenals; Adult; Affect; Androst-4-en-17beta-ol-3-one; Animals; Apoptosis; Apoptosis Pathway; Apoptotic; Binding Sites; Body Tissues; Breeding; CDDP; Cancer Patient; Cancer Treatment; Cancers; Cannot achieve a pregnancy; Cell Death, Programmed; Cell Locomotion; Cell Migration; Cell Movement; Cellular Migration; Chemicals; Chemotherapy Protocol; Chemotherapy Regimen; Chemotherapy, Cancer, General; Chemotherapy-Hormones/Steroids; Chemotherapy-Oncologic Procedure; Child; Child Youth; Children (0-21); Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatin; Cisplatina; Cisplatinum; Combination Chemotherapy Regimen; Combining Site; Consensus; Cysplatyna; DDP; DNA; Data; Delta4-androsten-17beta-ol-3-one; Deoxyribonucleic Acid; Development; Dichlorodiammineplatinum; Difficulty conceiving; Drugs; Endocrine Gland Secretion; Engineering; Engineerings; Epithelium; Fatty Tissue; Fecundability; Fecundity; Fertility; Fertility Rates; GFP; GHS-R type 1a; GHS-R1a; Gametes; Genes, p53; Genital System, Male, Testis; Germ Cells; Germ-Line Cells; Green Fluorescent Proteins; Hormones; Human, Adult; Human, Child; Immunoglobulin Enhancer-Binding Protein; Immunologic, Luciferase; Individual; Infertility; Investigation; Investigators; LTS; Lead; Life Style; Lifestyle; Long-Term Survivors; Luciferases; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Medical; Medication; Methods; Modeling; Monitor; Motility; Motility, Cellular; Muscle, Cardiac; Muscle, Heart; Myocardium; NF-kB; NF-kappa B; NF-kappaB; NFKB; Nuclear Factor kappa B; Nuclear Transcription Factor NF-kB; Organ; P53; Pathway interactions; Patients; Pb element; Peyrone`s Chloride; Peyrone`s Salt; Pharmaceutic Preparations; Pharmaceutical Preparations; Platinum Diamminodichloride; Platinum, Diaminedichloro-, cis- (8CI); Platinum, diamminedichloro-, (SP-4-2)-; Play; Prepuberal state; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Property; Property, LOINC Axis 2; Puberty; QOL; Quality of life; Quimioterapia; Radiation; Reactive Site; Receptor Protein; Reproductive Cells; Research Personnel; Researchers; Rodent Model; Role; Sex Cell; Sperm; Sperm Count; Sperm Count Procedure; Sperm Numbers; Spermatozoa; Staging; Survivors, Long-Term; TP53; TP53 gene; TRP53; Testicles; Testing; Testis; Testosterone; Therapeutic Hormone; Therapeutic Testosterone; Time; Tissues; Trans-Testosterone; Transcription Factor NF-kB; Transgenic Mice; Tumor Protein p53 Gene; Work; ing; adipose; adult human (21+); anticancer therapy; base; cancer chemotherapy; cancer therapy; cardiac muscle; cell motility; chemotherapeutic agent; chemotherapy; children; cis dichlorodiammineplatinum; cis platinum compound; cis-Diaminedichloroplatinum; cis-Diamminedichloroplatinum; cis-Diamminedichloroplatinum(II); cis-Dichlorodiammineplatinum(II); cis-Platinum; design; designing; drug/agent; experiment; experimental research; experimental study; ghrelin; gonad function; gonadal function; growth hormone secretagogue receptor type 1a; heart muscle; heavy metal Pb; heavy metal lead; human puberty; improved; infertile; initial cell; intervention effect; kappa B Enhancer Binding Protein; male; malignancy; men; men`s; neoplasm/cancer; novel; nuclear factor kappa beta; pathway; prepuberty; prevent; preventing; pup; ray (radiation); receptor; receptor, growth hormone secretagogue 1a; reproductive; research study; sexual cell; social role; sperm cell; suprarenal gland; unable to bear children; white adipose tissue; yellow adipose tissue; youngster; zoosperm
Relevance: 7. A significant proportion of children and men receiving chemotherapy for the treatment of cancer suffer damage to their reproductive organs leading to infertility. We currently do not have a way to prevent or predict who will become infertile after receiving chemotherapy; however, our preliminary work shows for the first time that a new hormone called "ghrelin" prevents this damage to the reproductive organs due to chemotherapy. The experiments we propose here will determine the effects of ghrelin on fertility and will lead us to the development of new ways to prevent or treat infertility
Project start date: 2009-09-03
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PA-06-181
5R21HD060870-02 (2010): $191858
1R21HD060870-01A1 (2009): $223295