CRHR1

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Corticotropin-releasing factor receptor 1 precursor (CRF-R-1) (CRF-R1) (CRFR-1) (Corticotropin-releasing hormone receptor 1) (CRH-R-1) (CRH-R1) [CRFR] [CRFR1] [CRHR]

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Koolen-de Vries Syndrome: Clinical Report of an Adult and Literature Review.

Koolen-de Vries syndrome (KdS) is a rare genetic condition characterized by typical facial dysmorphisms, cardiac and renal defects, skeletal anomalies, developmental delay, and intellectual disability of variable level. It is caused by a 440-680-kb deletion in the 17q21.31 region, encompassing CRHR1, MAPT, IMP5, STH, and KANSL1, or by an intragenic KANSL1 mutation. The majority of the patients reported are pediatric or young adults, and long-term studies able to define the prognosis of the disease are lacking. Here, we report a patient in the fourth decade misdiagnosed in the past as classical Ehlers-Danlos syndrome for the presence of generalized joint hypermobility, who carried a 546-kb deletion in 17q21.31, and compare his phenotype with those of the few KdS adults (aged >18 years) described so far. We observed a favorable prognosis of epilepsy and cardiovascular signs and reduction of joint hypermobility with age, thus providing insight into the natural history of the disorder.

MeSH Terms

  • Abnormalities, Multiple
  • Adolescent
  • Adult
  • Aging
  • Child
  • Chromosome Deletion
  • Chromosomes, Human, Pair 17
  • Delayed Diagnosis
  • Developmental Disabilities
  • Diagnostic Errors
  • Ehlers-Danlos Syndrome
  • Epilepsy
  • Female
  • Humans
  • Intellectual Disability
  • Male
  • Middle Aged
  • Phenotype
  • Prognosis
  • Young Adult


Influence of social environment on loneliness in older adults: Moderation by polymorphism in the CRHR1.

Both adverse social environments and genetic factors contribute to loneliness in old age. Mixed findings between older adults' social relations with their children and their levels of loneliness suggested that a gene × social environment interaction may be operating. We examine whether the effects of infrequent contact with children and low levels of perceived social support from children on loneliness in older adults are moderated by two candidate single nucleotide polymorphisms (i.e., rs1876831 and rs242938) in the corticotrophin releasing hormone receptor 1 (CRHR1) gene. This was a longitudinal observational study. and A population-based sub-sample of 1,374 community-dwelling older adults aged 65 years and older was examined from both the 2003-2004 and 2006-2007 English Longitudinal Study of Aging assessments. Our main outcome measure is loneliness, which was assessed by four items extracted from the ULCA loneliness scale. Compared with older adults carrying the CT/TT genotypes, individuals homozygous for the C allele of rs1876831 reported higher levels of loneliness in the context of infrequent social contact with children and lower levels of perceived social support from children. No gene × social environment interactions were found for loneliness between rs242938 and an adverse social environment related to children. This study provides the first evidence in humans that the CRHR1 gene interacts with exposure to a negative social environment to predict loneliness in older adults.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Aging
  • Alleles
  • Female
  • Gene-Environment Interaction
  • Homozygote
  • Humans
  • Loneliness
  • Longitudinal Studies
  • Male
  • Parent-Child Relations
  • Polymorphism, Single Nucleotide
  • Receptors, Corticotropin-Releasing Hormone
  • Social Environment
  • Social Support

Keywords

  • CRHR1
  • ELSA
  • gene–environment interaction
  • loneliness
  • social environment


Stress responsiveness of the hypothalamic-pituitary-adrenal axis: age-related features of the vasopressinergic regulation.

The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) into pituitary portal system; CRH and AVP stimulate adrenocorticotropic hormone (ACTH) release through specific G-protein-coupled membrane receptors on pituitary corticotrophs, CRHR1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response to ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory, and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates.


Keywords

  • V1b receptors
  • aging
  • hypothalamic–pituitary–adrenal axis
  • stress
  • vasopressin


Aging-related changes in cutaneous corticotropin-releasing hormone system reflect a defective neuroendocrine-stress response in aging.

Skin, being a mirror of the body, is a major target for aging research. Aging is a complex process that involves the decline of function or dysfunction of many systems. The corticotropin-releasing hormone (CRH) system is involved in skin inflammation. In addition, CRH has a suggested role in age-associated conditions and in animal aging models. However, a consistent logic interaction between the different CRH system components and the aging process has, to our knowledge, never been examined before. The expression of CRH, CRH-binding protein ([[CRHBP]]), CRH receptor 1 (CRHR1), and CRH receptor 2 ([[CRHR2]]) in healthy skin samples of 42 patients of different ages (18-92 years) was evaluated by immunohistochemistry, and the age-related changes were assessed. Compared with young skin, the aged skin displayed an upregulation of CRH in sebaceous glands and CRHR1 in hair follicles and the epidermis. Moreover, age-associated downregulation of [[CRHBP]] in the sebaceous and sweat glands was detected, whereas the [[CRHR2]] showed no age-related changes. Our findings suggest that the age-associated changes in the expression of CRH system components reflect an exaggerated stress response reaction, putting the aged skin continuously in a stress-like situation.

MeSH Terms

  • Adult
  • Aged
  • Aging
  • Carrier Proteins
  • Corticotropin-Releasing Hormone
  • Female
  • Humans
  • Male
  • Middle Aged
  • Receptors, Corticotropin-Releasing Hormone
  • Sebaceous Glands
  • Skin
  • Stress, Physiological
  • Young Adult


Corticotropin-releasing hormone receptor-1 in cerebral microvessels changes during development and influences urocortin transport across the blood-brain barrier.

In this study we tested the hypothesis that receptor-mediated transport of urocortin across the blood-brain barrier (BBB) undergoes developmental changes. Urocortin is a peptide produced by both selective brain regions and peripheral organs, and it is involved in feeding, memory, mood, cardiovascular functions, and immune regulation. In BBB studies with multiple-time regression analysis, we found that neonatal mice had a significant influx of (125)I-urocortin. By contrast, adult mice did not transport urocortin across the BBB. Quantitative RT-PCR showed that corticotropin-releasing hormone receptor (CRHR)-1 was developmentally regulated in enriched cerebral microvessels as well as hypothalamus, being significantly higher in neonatal than adult mice. This change was less dramatic in agouti viable yellow mice, a strain that develops adult-onset obesity. The level of expression of CRHR1 mRNA was 33-fold higher in the microvessels than in hypothalamic homogenates. The mRNA for [[CRHR2]] was less abundant in both regions and less prone to changes with development or the agouti viable yellow mutation. Supported by previous findings of receptor-mediated endocytosis of urocortin, these results suggest that permeation of urocortin across the BBB is dependent on the level of CRHR1 expression in cerebral microvessels. These novel findings of differential regulation of CRH receptor subtypes help elucidate developmental processes in the brain, particularly for the urocortin system.

MeSH Terms

  • Aging
  • Animals
  • Animals, Newborn
  • Blood-Brain Barrier
  • Female
  • Hypothalamus
  • Iodine Radioisotopes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microvessels
  • Protein Isoforms
  • Receptors, Corticotropin-Releasing Hormone
  • Urocortins


Candidate genes for respiratory disease associated with markers of inflammation and endothelial dysfunction in elderly men.

Inflammation and endothelial dysfunction are important risk factors for cardiovascular disease (CVD). We hypothesized that candidate genes selected for a study of asthma and chronic obstructive pulmonary disorder (COPD) are associated with markers of systemic inflammation and endothelial dysfunction in an aging population. Plasma levels of circulating C-reactive protein (CRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were obtained from 679 elderly male participants in the Normative Aging Study. Blood samples were analyzed for 202 single nucleotide polymorphisms (SNPs) in 25 candidate genes and included both haplotype tagSNPs and functional SNPs based on literature review. Data were stratified into discovery and replication cohorts for 2-stage analysis. In the discovery cohort, the relationship between biomarker level and genotype was analyzed using linear mixed effects with random intercepts for each subject and models were adjusted for age and BMI. A positive outcome in the discovery cohort was defined as a p-value <0.1 for the SNP. SNPs that met this criterion were analyzed in the replication cohort and confirmed for those which met a criterion of significance (p<0.025). In our analyses, SNPs in the CRHR1, ITPR2, and VDR genes met significance criteria. Our results suggest that genes thought to play a role in the pathogenesis of asthma and COPD may influence levels of serum markers of inflammation and endothelial dysfunction via novel SNP associations which have not previously been associated with cardiovascular disease.

MeSH Terms

  • Aged
  • Aging
  • Asthma
  • Biomarkers
  • C-Reactive Protein
  • Cardiovascular Diseases
  • Cohort Studies
  • Fibrinogen
  • Humans
  • Inflammation
  • Intercellular Adhesion Molecule-1
  • Male
  • Polymorphism, Single Nucleotide
  • Pulmonary Disease, Chronic Obstructive
  • Respiration Disorders
  • Vascular Cell Adhesion Molecule-1