7 research outputs found
Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease
Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease
Dynamic Combinatorial Mass Spectrometry Leads to Inhibitors of a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase
Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib
Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib
Crizotinib
(<b>1</b>), an anaplastic lymphoma kinase (ALK) receptor tyrosine
kinase inhibitor approved by the U.S. Food and Drug Administration
in 2011, is efficacious in ALK and ROS positive patients. Under pressure
of crizotinib treatment, point mutations arise in the kinase domain
of ALK, resulting in resistance and progressive disease. The successful
application of both structure-based and lipophilic-efficiency-focused
drug design resulted in aminopyridine <b>8e</b>, which was potent
across a broad panel of engineered ALK mutant cell lines and showed
suitable preclinical pharmacokinetics and robust tumor growth inhibition
in a crizotinib-resistant cell line (H3122-L1196M)
Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib
Crizotinib
(<b>1</b>), an anaplastic lymphoma kinase (ALK) receptor tyrosine
kinase inhibitor approved by the U.S. Food and Drug Administration
in 2011, is efficacious in ALK and ROS positive patients. Under pressure
of crizotinib treatment, point mutations arise in the kinase domain
of ALK, resulting in resistance and progressive disease. The successful
application of both structure-based and lipophilic-efficiency-focused
drug design resulted in aminopyridine <b>8e</b>, which was potent
across a broad panel of engineered ALK mutant cell lines and showed
suitable preclinical pharmacokinetics and robust tumor growth inhibition
in a crizotinib-resistant cell line (H3122-L1196M)