In this project we seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. The role of stress-related hormones in normal and disease states is being examined, and clinical applications for these hormones are sought. Several developmental/psychiatric disoders, including melancholic depression and anorexia nervosa have been associated with increased corticotropin-releasing hormone (CRH) secretion. We recently demonstrated that the postpartum blues/depression syndrome is characterized by transient profound hypoactivity of the stress system, which explains not only the mood disorder but also the propensity of these patients to develop autoimmune diseases. We also found the hCRH gene 5' regulatory region responds positively to estrogens, providing a potential explanation for the sexual dimorphism of psychiatric diseases characterized by aberrations in CRH secretion. We are currently performing preclinical studies with a newly discovered nonpeptide, oral CRH antagonist, antalarmin. Glucocorticoid resistance is an autosomal recessive or dominant disease associated with abnormalities of the glucocorticoid receptor. We have elucidated the molecular pathophysiology of this syndrome by defining mutations and/or deletions of the glucocorticoid receptor gene leading to abnormal or decreased receptors in the tissues of patients. The mineralocorticoid receptor and the subunits of the amiloride-sensitive sodium channel were studied in sporadic cases of pseudohypoaldosteronismor mineralocorticoid resistance and the defect was localized in the beta and gamma subunits of this channel. The interactions of the classic glucocorticoid receptor (GRalpha) and its nonligand binding natural homolog glucocorticoid receptor delta (Grdelta) with each other and with the heat-shock proteins and glucocorticoid-responsive elements (GREs) of the DNA are studied, as well as the importance of GRdelta in human physiology and pathophysiology. We have found an abnormal expression of the beta vs. the alpha isoform of the glucocorticoid receptor in patients with glucocorticoid resistant asthma. We have determined that Vpr, a 15KD protein product of HIV-1, is a coregulator of the glucocorticoid, androgen and estrogen receptors, the presence of which explain some of the clinical features and pathogenesis of AIDS. We have elucidated the molecular pathophysiology of hereditary ACTH resistance, an autosomal recessive disorder characterized by isolated glucocorticoid deficiency, by defining abnormalities of the ACTH receptor gene. We have elucidated the molecular pathophysiology of testicular and ovarian resistance to luteinizing hormone (LH) by defining abnormalities of the LH receptor gene. We have localized the gene for Carney Complex, a multiple neoplasia/lentiginosis syndrome, on chromosome 2p16, and have characterized it as a protooncogene. We have defined the molecular defect in the excessive aromatase syndrome, a novel promoter aberrantly and ectopically expressed.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Intramural Research (Z01)
Project #
1Z01HD000618-16
Application #
6162434
Study Section
Special Emphasis Panel (DEB)
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
1997
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Kino, T; Charmandari, E; Chrousos, G P (2011) Glucocorticoid receptor: implications for rheumatic diseases. Clin Exp Rheumatol 29:S32-41
Nader, Nancy; Chrousos, George P; Kino, Tomoshige (2009) Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J 23:1572-83
Maheu, Francoise S; Merke, Deborah P; Schroth, Elizabeth A et al. (2008) Steroid abnormalities and the developing brain: declarative memory for emotionally arousing and neutral material in children with congenital adrenal hyperplasia. Psychoneuroendocrinology 33:238-45
Mueller, S C; Temple, V; Oh, E et al. (2008) Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH). Psychoneuroendocrinology 33:973-80
Merke, Deborah P (2008) Approach to the adult with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 93:653-60
Shrivastav, Shashi; Kino, Tomoshige; Cunningham, Tshaka et al. (2008) Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy. Mol Endocrinol 22:234-47
Charmandari, Evangelia; Kino, Tomoshige; Ichijo, Takamasa et al. (2007) A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. J Clin Endocrinol Metab 92:3986-90
Ernst, Monique; Maheu, Francoise S; Schroth, Elizabeth et al. (2007) Amygdala function in adolescents with congenital adrenal hyperplasia: a model for the study of early steroid abnormalities. Neuropsychologia 45:2104-13
Bai, Xueyan; Wu, Jun; Zhang, Qiuyang et al. (2007) Third-generation human mitochondria-focused cDNA microarray and its bioinformatic tools for analysis of gene expression. Biotechniques 42:365-75
Kino, Tomoshige; Ichijo, Takamasa; Amin, Niranjana D et al. (2007) Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: clinical implications for the nervous system response to glucocorticoids and stress. Mol Endocrinol 21:1552-68

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