A5008284651- Hormonal Regulation and Hypertension
- Sexual Differentiation and Disorders
- Hypothalamic control of reproductive hormones
- Adrenal Hormones and Disorders
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Cancer, Hypoxia, and Metabolism
- Adrenal and Paraganglionic Tumors
- Growth Hormone and Insulin-like Growth Factors
- Congenital heart defects research
- Glioma Diagnosis and Treatment
- Pluripotent Stem Cells Research
- Stress Responses and Cortisol
- Reproductive Biology and Fertility
- Fibroblast Growth Factor Research
- Ovarian cancer diagnosis and treatment
- Erythrocyte Function and Pathophysiology
- Protein Degradation and Inhibitors
- Nuclear Structure and Function
- Melanoma and MAPK Pathways
- Metabolism, Diabetes, and Cancer
- Cellular transport and secretion
- Microtubule and mitosis dynamics
- Genetics and Neurodevelopmental Disorders
- Mechanisms of cancer metastasis
- Sperm and Testicular Function
University Hospital Carl Gustav Carus
2018-2025
Boston Children's Hospital
2019-2025
Harvard University
2020-2025
Harvard Stem Cell Institute
2019-2023
University Hospital of Bern
2022
Queen Mary University of London
2015-2021
William Harvey Research Institute
2016-2021
TU Dresden
2018-2021
Universitat Autònoma de Barcelona
2011-2016
Research Article13 April 2016Open Access Source DataTransparent process IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty Sasha R Howard Centre for Endocrinology, William Harvey Institute, Barts and the London School of Medicine Dentistry, Queen Mary University London, UK Search more papers by this author Leonardo Guasti Gerard Ruiz-Babot Alessandra Mancini Alessia David Integrative Systems Biology Bioinformatics, Department Life...
Activating mutations in the canonical Wnt/β-catenin pathway are key drivers of hyperplasia, gateway for tumor development. In a wide range tissues, this occurs primarily through enhanced effects on cellular proliferation. Whether additional mechanisms contribute to β-catenin-driven hyperplasia remains unknown. The adrenal cortex is an ideal system which explore question, as it undergoes following somatic β-catenin gain-of-function (βcat-GOF) mutations. Targeting βcat-GOF zona Glomerulosa...
Adrenal insufficiency is managed by hormone replacement therapy, which far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for curative approach restoring complex feedback regulation of hypothalamic-pituitary-adrenal axis. Here, we generated human induced (hiSCs) fibroblasts, blood-, and urine-derived through forced expression factor-1 activation PKA LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells,...
The mitogen-activated protein (MAP) kinase extracellular signal-regulated 5 (ERK5) plays a crucial role in cell proliferation, regulating gene transcription. ERK5 has unique C-terminal tail which contains transcriptional activation domain, and activates transcription by phosphorylating factors acting itself as coactivator. However, the molecular mechanisms that regulate its nucleocytoplasmatic traffic are unknown. We have used tandem affinity purification to identify proteins interact with...
Abstract Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics ACC has hampered progress in field. We analyzed Cancer Genome Atlas (TCGA) dataset for found patients harboring alterations both p53/Rb Wnt/β-catenin signaling pathways show worse prognosis compared harbored only one. To model this, we utilized Cyp11b2(AS) Cre line to generate mice adrenocortical-specific activation, Trp53...
Adrenocortical carcinoma (ACC) is a rare malignancy with no widely available biomarkers and commonly presents at later stages bleak prognosis [1]. Dysregulation of signaling pathways involved in the organogenesis homeostasis adrenal cortex implicated its pathogenesis [2]. The paternally expressed, cleavable protein delta-like non-canonical Notch ligand 1 (DLK1) expressed rat adrenocortical progenitor cells [3] clusters relatively undifferentiated human gland [4]. Its expression most adult...
Abstract Context Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP sometimes seen relatives of patients with hypogonadotropic hypogonadism (HH), mutations genes known to cause HH that segregate trait familial self-limited have not yet been identified. Objective To assess contribution phenotype DP. Design, Patients, and Setting We performed whole-exome sequencing 67 probands 93 from a large cohort DP, validated...
3-Phosphoinositide-dependent protein kinase 1 (PDK1) operates in cells response to phosphoinositide 3-kinase activation and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] production by activating a number of AGC kinases, including B (PKB)/Akt. Both PDK1 PKB contain pleckstrin homology (PH) domains that interact with the PtdIns(3,4,5)P(3) second messenger. Disrupting interaction PH domain phosphoinositides expressing K465E knock-in mutation resulted mice reduced activation. We...
Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and be difficult to diagnose. We undertook next generation sequencing in cohort of children young adults PAI unknown etiology from around the world identified heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) CYP11A1 19 individuals 13 different families (allele frequency within undiagnosed our cohort, 0.102 vs 0.0026 Genome Aggregation Database; P < 0.0001)....
Abstract Adrenal insufficiency requires lifelong corticoid replacement therapies. However, current therapies are not able to replace the physiological circadian pattern of adrenal cortex and associated with many metabolic, vascular, neuroendocrine, mental perturbations. Therefore, regenerative more curative strategies would be desirable. In perspective, we describe emerging new for treatment insufficiency. particular, discuss gene therapy cell strategies. Furthermore, how cells might used as...
Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in dose- and time-dependent manner. Establishing cell-based therapy would provide physiologically responsive approach for treatment of this condition. We report generation large numbers human-induced steroidogenic cells (hiSCs) human pluripotent stem (hPSCs). Directed differentiation hPSCs into hiSCs recapitulates initial stages development. Following expression factor 1, activation...
Encapsulation of primary bovine adrenocortical cells in alginate is an efficacious model a bioartificial adrenal cortex. Such cortex can be used for the restoration lost function vivo as well vitro modeling microenvironment and investigation cell–cell interactions adrenals. The aim this work was optimization cortex, that generation highly productive, self-regenerating, long-term functioning immune tolerant organ. To achieve this, it necessary stem progenitor are present gland, these...
Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed discover important underlying regulators puberty through interrogation GnRH pathways. Whole exome sequencing (WES) data consisting 193 individuals, 100 families with puberty, was analysed using virtual panel genes related development and function (n = 12). Five rare predicted deleterious...
Abstract Primary adrenal insufficiency is a life‐threatening disorder, which requires lifelong hormone replacement therapy. Transplantation of xenogeneic cells potential alternative approach for the treatment insufficiency. For successful outcome this therapy, transplanted should provide adequate secretion and respond to physiological stimuli. Here, we describe generation characterization primary porcine spheroids capable replacing function glands in vivo. Cells within morphologically...
Abstract Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated cancer initiation, progression, recurrence. The adrenal cortex a dynamic that undergoes life-long turnover. Here, using genetic fate mapping murine adrenocortical carcinoma (ACC) models, we have identified population stem cells express delta-like non-canonical Notch ligand 1 (DLK1). These are active during development, near dormant postnatally but re-expressed ACC. In study...
This whole-exome study in 67 probands and 93 relatives from a large cohort of familial delayed puberty identifies new heterozygous HS6ST1 mutation as novel cause puberty.
Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | 1479-6848 (online)
Primary or secondary adrenal insufficiency (AI) results from failure impairment of the hypothalamic-pituitary axis, respectively. The most frequent cause primary AI is autosomal recessive congenital hyperplasia (CAH). Patients with need life-long treatment exogenous steroids, which can be challenging, given that currently available formulations do not mimic physiologic cortisol secretion. ability to generate donor-specific and functional adrenocortical-like cells would facilitate: (1) next...