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. The discovery of the structure of corticotropin releasing hormone (CRH) and the development of sensitive assays for measuring HPA- and HPG-related hormones and their receptors have led to rapid progress in this field. Major progress has been made in three areas: 1) Clinical applications of CRH: An ovine (o) CRH stimulation test has been developed that is useful in the differential diagnosis of adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states (psychiatric hypercortisolism). The oCRH test and/or measurements of CSF CRH have increased our understanding of the pathophysiology of Cushing's syndrome, melancholic depression, childhood sexual abuse, atypical/seasonal depression, the chronic fatigue/fibromyalgia syndromes, diabetes mellitus, rheumatoid arthritis, and the postpartum blues/depression syndromes. 2) The regulation of the axis by neurotransmitters, neuropeptides, and glucocorticoids has been studied in vivo and/or in vitro. Third trimester pregnant women and athletes have a hyperfunctional pituitary-adrenal axis in the resting state. The hCRH gene 5' regulatory region has been cloned and sequenced and its regulation has been studied. It has 2 active promoters and responds positively to estrogens, providing a potential explanation for the sexual dimorphism of psychiatric diseases characterized by aberrations in CRH secretion. 3) Roles and actions of HPA and HPG axes hormones. 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 deletion 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 are studied in sporadic cases of pseudohypoaldosteronism or mineralocorticoid resistance. The interaction of the classic glucocorticoid receptor (GRalpha) and its nonligand binding natural homolog glucocorticoid receptor beta (GRbeta) with each other and with the heat-shock proteins and glucocorticoid-responsive elements (GREs) of the DNA are studied, as the well as the importance of GR~ in human physiology and pathophysiology. 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.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
1995
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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