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Gene identification and molecular regulatory mechanisms responsible for LH-induced Adrenal gland pathologies

Objetivo

Gonadotrophins, including Latinising hormone (LH), are key hormones regulating gonad functions. LH actions on target cells are mediated by a specific receptor, the LH receptor (LHR). A very perplexing finding has been the recent discovery of functional LHR in extragonadal tissues, e.g. in the adrenal gland which suggests some as yet unknown non-gonad functions for LH. Experimental models showed that elevated LH levels lead to LHR over-expression in the adrenals, resulting in hyperplasic and cancer. This is reminiscent of various adrenal diseases occurring concomitantly to increased LH levels in some, but not a postmenopausal women, such as hirsute, Cushing\\\'s syndrome, adrenal hyperplasic and tumours obesity and even osteoporosis. A relevant question is \\\"why do high levels of LH induce adrenalhyperfunction in some cases and not in others? \\\" To address this question, non-genetically modified mice of various genetic backgrounds will be used in order to study the occurrence of LH-dependent adrenalreponsiveness secondary to gonadectomy, which mimics the postmenopausal status. The objectives of my application are to address the molecular regulatory mechanisms involved in LH actions on adrenals. My proposal is articulated around three main axes, using multidisciplinary genomic approaches:
-First, I will determine the number of candidate genes (and if possible their identity) potentially involved in the appearance of the adrenal phenotype in mice developing the disease.
-Second, an extensive study of adrenal LHR gene expression in selected mouse strains will be performed, will search for mutations/polymorphism in the LHR promoter correlated with LHR over-expression unresponsive adrenals, and I will study the regulation of its expression. -Third, I will perform micro-array analysis to identify the genes whose LHR-induced expression leads to adrenal hyperplasic.

Convocatoria de propuestas

FP6-2002-MOBILITY-5
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Coordinador

INSTITUTE OF REPRODUCTIVE AND DEVELOPMENTAL BIOLOGY - IMPERIAL COLLEGE OF LONDON
Aportación de la UE
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Dirección
Du Cane Road
LONDON
Reino Unido

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