دانلود کتاب Nuclear Receptors in Human Health and Disease

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Introduction Nuclear Receptors: The Past, the Present and the Future Overview Contents Part I: Reproduction and Development 1: Nuclear Receptors in Pregnancy and Outcomes: Clinical Perspective 1.1 Introduction 1.2 The Role of Nuclear Receptors in Maintaining a Healthy Pregnancy 1.2.1 Progesterone Receptors and PPARS in Early Pregnancy 1.2.2 Liver-X-Receptors, Clock Genes and Maternal Metabolic Adaptations in Mid-to-Late Pregnancy 1.2.3 Parturition 1.3 Nuclear Receptors and Gestational Disorders 1.3.1 Gestational Diabetes Mellitus 1.3.2 Intrahepatic Cholestasis of Pregnancy 1.3.3 Pre-eclampsia 1.3.4 Spontaneous Preterm Labour 1.4 Conclusions References 2: Female Reproductive Systems: Hormone Dependence and Receptor Expression 2.1 Introduction 2.2 Anatomy of the Female Reproductive System 2.2.1 Ovaries 2.2.2 Fallopian Tubes 2.2.3 Uterus 2.2.4 Cervix and Vagina 2.3 Hormone Biosynthesis and Metabolism Within the Female Reproductive System 2.3.1 Endocrine – Ovary 2.3.2 Intracrine 2.4 Expression and Action of Steroid Receptors Within the Female Reproductive System 2.4.1 Oestrogen Receptors 2.4.2 Progesterone Receptors 2.4.3 Androgen Receptor 2.5 Summary and Future Prospects References 3: Nuclear Receptors in Ovarian Function 3.1 Introduction 3.2 Hormonal Control of Dynamic Physiological Change in the Ovary 3.3 Physiological Effects of Nuclear Hormone Receptors on Ovarian Functions 3.4 Signalling Mechanism of Nuclear Receptors in the Ovary 3.5 Conclusions References Part II: Metabolism 4: Nuclear Receptors in Energy Metabolism 4.1 Introduction and Outline 4.2 Liver 4.2.1 PPARα Is the Key to Liver Lipid Metabolism 4.2.2 LXR and FXR Are Regulators of Cholesterol Metabolism 4.2.3 GR – Linking Inflammation and Metabolism 4.3 Adipose Tissue 4.3.1 PPARγ Is the Master Regulator of Adipose Tissue Function 4.4 Muscle 4.4.1 PPARβ/δ – Regulator of Skeletal Muscle 4.5 Pancreas 4.5.1 The NR4A Family of Orphan Nuclear Receptors as Regulators of β-Cell Physiology 4.6 Conclusion References 5: Nuclear Receptors and Lipid Sensing 5.1 The Molecular Biology of Lipid-Sensing Nuclear Receptors 5.1.1 Liver x Receptors (NR1H2, NR1H3) 5.1.1.1 Structure of the LXRs 5.1.1.2 Endogenous Selective Modulators of LXR 5.1.1.3 Fine-Tuning of LXR Signaling 5.1.2 Farnesoid x Receptor Alpha (NR1H4) 5.1.2.1 Structure of FXR 5.1.2.2 FXR Ligands 5.1.2.3 Fine-Tuning of FXR Signaling 5.1.3 Peroxisome Proliferator-Activated Receptors (NR1C1, NR1C2, NR1C3) 5.1.3.1 Structure of PPARs 5.1.3.2 PPAR Ligands 5.1.3.3 Fine-Tuning of PPAR Signaling 5.1.4 Other Lipid-Sensing NR 5.2 Emerging Trends for Lipid-Sensing Nuclear Receptors 5.2.1 Cancer Theranostics 5.2.1.1 LXR in Breast and Prostate Cancer 5.2.1.2 FXR in Cancer 5.2.1.3 PPAR in Cancer 5.2.2 Lipid-Sensing Nuclear Receptors and Immuno-Oncology 5.2.3 Therapeutic ligands Targeting Lipid-Sensing Nuclear Receptors 5.3 Perspectives References Part III: Central Systems 6: Corticosteroid Receptors in Cardiac Health and Disease 6.1 Introduction 6.2 MR and Heart Failure 6.3 GR Limits Cardiac Injury and Subsequent Pathophysiology 6.4 Glucocorticoid Action in Heart Is Sexually Dimorphic 6.5 Cardiac Injury and Repair: The Balance of GR and MR Action as a Determinant of Cell Death or Survival 6.6 Glucocorticoids Regulate calcium Handling and Metabolism in Cardiomyocytes 6.7 Early Life Programming of Cardiovascular Disease: Creating Vulnerability? 6.8 Concluding Remarks and Future Perspectives References 7: Physiological Convergence and Antagonism Between GR and PPARγ in Inflammation and Metabolism 7.1 Introduction 7.2 GR and PPARγ in Monocytes and Macrophages 7.3 GR and PPARγ in Non-Macrophage Immune Cell Subsets 7.3.1 T Cells 7.3.2 Dendritic Cells (DCs) 7.4 GR and PPARγ in Adipocytes 7.5 GR and PPARγ in the Liver 7.6 Concluding Remarks References 8: Circadian Rhythm and Nuclear Receptors 8.1 Ligands and NR Expression Through Time 8.2 Circadian Clocks 8.2.1 Clocks, Entrainment and Misalignment 8.3 Nuclear Receptors Within the Clock 8.4 Circadian Impacts of NHR Function 8.5 Nuclear Hormone Receptor Chronotherapeutics 8.6 Conclusions References 9: Vitamin D and Gut Health 9.1 Introduction 9.2 Classical Role of Vitamin D as a Regulator of Intestinal Ca Absorption 9.3 Gut Absorption and Excretion of Vitamin D 9.4 Cellular Targets of Vitamin D Action in the Intestine 9.5 Conclusions References Part IV: Cancer 10: Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer 10.1 Introduction to Estrogen Receptor 10.1.1 Structure 10.1.2 Functional Domains 10.1.3 Genomic Signaling 10.1.4 Estrogen Response Elements and Gene Regulation 10.1.5 Normal Physiologic Functions and Tissue Expression 10.2 Wild-Type ERα in Breast Cancer 10.2.1 Prognostic and Predictive Implications 10.2.2 Molecular Subtypes or Heterogeneity in ER Positive 10.2.3 Evidence for Tumorigenic Signaling 10.2.4 Ligand-Independent Activation Through Phosphorylation 10.2.5 Downstream Redirection via Transcription Factors 10.3 Endocrine Treatment & Resistance in Breast Cancer 10.3.1 Overview of Therapies Targeting ER 10.3.2 Mechanisms of Endocrine Resistance 10.4 ESR1 Mutations in Breast Cancer 10.4.1 Types of Genomic Alterations 10.4.2 ESR1 Ligand Binding Domain Mutations 10.4.3 Endocrine Resistance and Cellular Phenotypes 10.4.4 cfDNA Analysis of Clinical Trials 10.4.5 Preclinical Evaluation of Therapeutic Vulnerabilities 10.4.6 Future Directions for Treatment References 11: AR Structural Variants and Prostate Cancer 11.1 The Androgen Receptor and Its Role in Prostate Cancer 11.2 Discovery of the AR-Vs 11.3 Regulation of AR-V Expression 11.4 Biological Activity and Function of AR-Vs 11.5 AR-V Prevalence and Significance in Disease 11.6 Therapeutically Targeting AR-Vs 11.7 Inhibition of the AR N-Terminal Domain 11.8 Inhibition of the AR-DBD 11.9 Degradation of AR 11.10 Concluding Remarks References 12: ERβ and Inflammation 12.1 Colon Inflammation and Colorectal Cancer 12.1.1 Pro-Inflammatory Signaling 12.2 Estrogen Signaling in Colon Inflammation and CAC 12.3 Expression Pattern and Role of ERβ in Colon 12.3.1 Intestinal Epithelial ERβ Regulates Core Clock Genes 12.3.2 Intestinal Epithelial ERβ Regulates NFκB Signaling and Gut Microbiota 12.4 Concluding Remarks References 13: Genomic Insights into Non-steroidal Nuclear Receptors in Prostate and Breast Cancer 13.1 Nuclear Receptor Genomic Interactions Are Highly Integrated and Sense a Wide Variety of Inputs 13.2 Genomic Interactions of Non-steroidal Nuclear Receptors in PCa and BrCa 13.2.1 The Vitamin D Receptor 13.2.2 Retinoic Acid Receptors 13.2.3 RAR Related Orphan Receptor C 13.2.4 Peroxisome Proliferator-Activated Receptors 13.2.5 Hepatocyte Nuclear Factor 4 α and γ 13.2.6 COUP Transcription Factor I and II 13.2.7 NUR77 13.3 Mechanisms of NR Cooperation: Bookmarking Functions by Non-steroidal NRs 13.4 Genomic Approaches to Defining Type I and II NR Cistromes and Interactions 13.5 Conclusion References Part V: New Developments in Transcriptional Control by Nuclear Receptors 14: Protein Condensation in the Nuclear Receptor Family; Implications for Transcriptional Output 14.1 The Nuclear Receptor Superfamily 14.2 A Condensate Model for NR Transcriptional Regulation 14.3 Evidence of NR Condensate Formation 14.4 Potential Condensate Formation of the NR Superfamily 14.5 Conclusion and Future Perspectives References 15: Prostate Cancer Epigenetic Plasticity and Enhancer Heterogeneity: Molecular Causes, Consequences and Clinical Implications 15.1 Introduction 15.2 Prostate Cancer as Enhancer-Driven Disease 15.3 AR Biology and Enhancer Regulation in Prostate Cancer 15.4 PCa-Specific Pioneer Factors as Source of Regulatory Heterogeneity in AR Binding 15.5 AR Cistromes are Heterogeneous Between Different Tissue, Cellular and Tumor Contexts 15.6 AR Cistromic Heterogeneity Progressively Develops from PCa Initiation to Neuroendocrine Differentiation 15.7 Metastatic PCa Heterogeneity 15.8 Non-coding and Protein Coding Somatic Mutations Induce AR Cistromic Heterogeneity 15.9 Risk SNPs and Somatic Mutations are Enriched at AR-Bound Enhancers 15.10 Clinical Implications and Biomarker Development of Heterogeneity in Epigenetic Subtypes 15.11 Future Outlook References 16: Epigenetic Coregulation of Androgen Receptor Signaling 16.1 Introduction 16.2 AR Structure and Coregulator Binding Interactions 16.3 AR-Coregulator Mediated Alteration of the Chromatin Landscape 16.3.1 Pioneer Factors 16.3.2 Nucleosome Remodellers 16.3.3 Histone Post-translational Modifiers 16.3.3.1 Histone Acetylases/Deacetylases 16.3.3.2 Histone Methylases/Demethylases 16.3.4 Epigenetic Readers 16.3.5 Chromatin Looping 16.4 Dysregulated Expression and Function of Coregulators Promotes PCa Progression by Multiple Mechanisms 16.5 Therapeutic Targeting of AR Epigenetic Coregulators 16.6 Conclusion References Part VI: Clinical Translation 17: Clinical Translation: Targeting the Estrogen Receptor 17.1 Looking Back: The Beginnings of Endocrine Targeting 17.2 The Advent of Small Molecule Modulators of ER Function 17.3 Alternative Strategies for Endocrine Suppression: Targeting the Ligand 17.4 In Pursuit of a Pure Antiestrogen 17.4.1 Prospective Optimization of ERα Degradation: Contemporary SERD/SERM Hybrids 17.4.2 Latest Generation ER Antagonists: The -Esterants 17.5 Novel Approaches to ER Antagonists: Heterobifunctional Degraders and Covalent Binders 17.6 Bringing It Back to the Biology: Neoadjuvant Studies as Potentially Valuable Testing Grounds 17.7 Outlook References 18: Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors 18.1 Introduction 18.2 Modular Structure of Nuclear Hormone Receptors 18.2.1 Intrinsically Disordered N-terminal Domain (NTD) 18.2.2 DNA-Binding Domain (DBD) and Hinge Region 18.2.3 Ligand-Binding Domain (LBD) 18.3 Androgen Receptor 18.4 Rationale for Developing Inhibitors to the NTD 18.5 Small Molecule Inhibitors of AR-NTD 18.6 First-in-Human Clinical Trials 18.7 Conclusions References 19: Genetic Variation and Mendelian Randomization Approaches 19.1 Introduction 19.1.1 GWAS on NR Levels 19.1.2 25 Hydroxyvitamin D (Calcidiol) 19.1.3 Thyroid Hormones (Thyroxin and Triiodothyronine) 19.1.4 Estradiol 19.1.5 Testosterone and its Precursors 19.1.6 Vitamin A 19.1.7 Cortisol 19.2 Discussion 19.2.1 Missing Heritability 19.2.2 Ethnic Representation 19.2.3 Limited Access to Measurements of Direct Ligands of NR 19.2.4 Functional Follow-Up 19.2.5 Future Clinical Applications References Index