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- Yu, Hao, et al.
(författare)
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Association of an estrogen-sensitive Pax1-Col11a1-Mmp3 signaling axis with adolescent idiopathic scoliosis.
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than five-fold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here we sought to define the roles of PAX1 and newly-identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 9,161 individuals with AIS and 80,731 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629_c.4004C>T; p.(Pro1335Leu); P=7.07e -11 , OR=1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice ( Pax1 -/- ). In postnatal spines we found that Pax1 and collagen (α1) XI protein both localize within the intervertebral disc (IVD)-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1 -/- spines compared to wildtype. By genetic targeting we found that wildtype Col11a1 expression in growth plate cells (GPCs) suppresses expression of Pax1 and of Mmp3 , encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, this suppression was abrogated in the presence of the AIS-associated COL11A1 P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 , or tamoxifen treatment, significantly altered Col11a1 and Mmp3 expression in GPCs. These studies support a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a Pax1 - Col11a1 - Mmp3 signaling axis in the growth plate.
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- Zhang, Guo-Qiang
(författare)
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Female sex hormones and health outcomes in women with specific focus on asthma
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In humans, gender differences exist across a wide spectrum of diseases. For instance, women are more likely to develop Sjogren’s syndrome, systemic lupus erythematosus, and autoimmune thyroid disease compared to men. On the other hand, men are more likely than women to develop coronary heart disease, Parkinson’s disease, and severe coronavirus disease 2019. These observations have led to the hypotheses that female sex steroid hormones (estrogens and progestogens) may play an important role in the pathogenesis of these diseases. Asthma is a heterogenous respiratory disease, affecting 1–18% of the population in different countries. For decades, an age- and gender-related switch in asthma has been reported across different continents. Before puberty, asthma is more common in boys than in girls. However, from adolescence and into adulthood, asthma becomes more common in women than in men. Although the switch in asthma from male to female predominance has been recognized for over 40 years, the evidence linking female sex hormones to asthma remains uncertain. This thesis aims to investigate the role of female sex hormones in women’s health, with a particular focus on asthma. The hormonal exposures of interest include age at menarche (age at first menstrual period) and menopause (age at last menstrual period), which are commonly used as proxy measures for endogenous female sex hormones, and the two widely used exogenous female sex hormones among women (hormonal contraceptives among reproductive-age women and menopausal hormone therapy [MHT] among menopausal women). In Paper I, we conducted an umbrella review, which synthesizes the evidence from previously published systematic reviews and meta-analyses, to obtain a comprehensive picture around the effects of MHT in menopausal women. Overall, we found that MHT had a complex balance of benefits and risks on diverse health outcomes. For instance, besides the alleviation of menopausal symptoms, use of MHT was associated with decreased risks of bone fracture, diabetes mellitus, esophageal cancer, gastric cancer, and colorectal cancer, but increased risks of stroke, venous thromboembolism, gallbladder disease, breast cancer, and ovarian cancer. The overall quality of the included systematic reviews was only moderate to poor. In Paper II, we conducted a matched case-control study to determine the effects of use of hormonal contraceptives and MHT on the risk of developing asthma in women. We found that use of hormonal contraceptives may reduce the risk of asthma in women, whereas use of MHT may increase the risk in menopausal women. In Paper III, we conducted a matched case-control study to investigate the effects of age at menarche and menopause on asthma risk. We found that early age at menarche was associated with an increased asthma risk. The relation of age at menopause to asthma risk in menopausal women was uncertain. In conclusion, female sex hormones can influence diverse health outcomes in women. The umbrella review provides a comprehensive tool for clinicians and patients to evaluate the trade-offs between the benefits and risks associated with MHT use in menopausal women. Further epidemiologic studies or clinical trials of female sex hormones and asthma across different populations are warranted to replicate our findings. Further mechanistic studies are needed to identify potential sex hormone-driven asthma endotypes as well as novel therapeutic targets, thereby providing the foundation for more individualized asthma prevention and treatment strategies.
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- Zhang, Qiang
(författare)
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Understanding p53 structure and targeting mutant p53 for improved cancer therapy
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The p53 gene family consists of p53, p63 and p73. The three proteins share a high degree of structural similarity in their DNA-binding domains but have rather different functions. The tumor suppressor p53 acts as the guardian of the genome and is activated in response to cellular stress. p53 is a transcription factor that activates downstream target genes to induce cell cycle arrest, senescence or apoptosis. However, the TP53 gene is inactivated by missense mutation in about half of human tumors. Therefore, reactivation of mutant p53 is an attractive strategy for novel cancer treatment. The mutant p53-reactivating compound PRIMA-1, identified in a cellular screen of the NCI Diversity set, suppresses tumor cell growth in a mutant p53-dependent manner. The methylated analog PRIMA-1Met, now named APR-246, is even more potent. APR-246 has been successfully tested in a phase I/IIa clinical trial. A phase II clinical trial in ovarian cancer is ongoing. Both PRIMA-1 and APR-246 are prodrugs that are converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds covalently to cysteines in p53's DNA-binding domain. In paper I, we tested the effect of APR-246 on primary adult skin keratinocytes with p63 mutations from patients with the EEC developmental syndrome. We showed that APR-246 can partially rescue morphological defects of the mutant p63-carrying EEC keratinocytes, and expression of differentiation and stratification markers. Furthermore, we found that APR-246 restored the expression of p63 target genes. Our findings demonstrate that APR-246 can also target mutant forms of p63. In paper II, we found that the Michael acceptor activity of MQ is critical for MQ binding, thermostabilization and refolding of mutant p53. We identified Cys277 as a prime binding site for MQ in p53. Cysteine to alanine substitution at this position abolished both MQ binding and thermostabilization. Moreover, we found that both Cys124 and Cys277 are required for APR-246 mediated mutant p53 reactivation in His175 mutant p53-carrying tumor cells. In paper III, we selected potential thiol-reactive compounds including Michael acceptors, primary alcohols, imines and aldehydes, with top p53 selectivity based on datamining of the NCI database. Multivariable analysis identified different functional groups associated with various features of mutant p53 reactivation. Michael acceptors are more prone to high toxicity and thiol reactivity. Alcohols and imines are more associated with p53 refolding. Aldehydes are more likely to stabilize p53. These results may facilitate the design of novel mutant p53-targeting compounds. Paper IV describes a p53-like gene in the hydrothermal annelid Alvinella pompejana. Sequence alignment and structure modeling indicated that this p53 homolog is more similar to p63 and p73. Consistent with this finding, the DNA-binding domain of Alvinella has high thermostability. We identified repacking features in the hydrophobic core of Alvinella p53 that are associated with its high thermostability. Understanding structural features of p53 family proteins that govern stability may provide insights for development of mutant p53-reactivating drugs.
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