NURTIENT RESTRICTION: FETAL BABOON RENAL DEVELOPMENT

营养限制：胎儿狒狒肾脏发育

• 批准号: 8129572
• 负责人: MARK J NIJLAND
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8129572
• 关键词: 1-Phosphatidylinositol 3-Kinase; 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adult; Affect; American; Anatomy; Angiotensins; Animals; Antibodies; Architecture; Aromatase; Biological; Biological Assay; Blood Vessels; Blood capillaries; CD31 Antigens; CYP17A1 gene; CYP19A1 gene; Cells; Chronic Kidney Failure; Collagen Type IV; Cytochrome P450; Data; Development; Diet; Electrophoretic Mobility Shift Assay; Endowment; Enzymes; Epidemiology; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Estrogens; Extracellular Matrix; Extracellular Matrix Proteins; Fetal Kidney; Fetus; Fibronectins; Foundations; Freezing; Gelatinase A; Gender; Gene Expression; Genes; Glomerular Capillary; Goals; Growth Factor; Growth Factor Receptors; HIF1A gene; Histology; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hypoxia Inducible Factor; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like-Growth Factor I Receptor; Intake; Kidney; Laminin; Length; Life; Life Style; Mediating; Mesenchymal; Messenger RNA; Mixed Function Oxygenases; Modeling; Nephrons; Nutrient; Organ; PDGFRB gene; Papio; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Phosphorylation; Placentation; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor beta Receptor; Predisposition; Pregnancy; Primates; Production; Protein Splicing; Regulation; Renin; Renin-Angiotensin System; Reporting; Sirolimus; Structure; System; Time; Tissues; Transcriptional Regulation; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transforming Growth Factors; Tubular formation; Type 2 Angiotensin II Receptor; Variant; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Western Blotting; angiogenesis; capillary; cell type; cytokine; density; detection of nutrient; feeding; fetal; gene environment interaction; human TGFB1 protein; in utero; insight; integrin-linked kinase; juvenile animal; kidney vascular structure; mRNA Expression; maternal nutrient restriction; matrigel; nephrogenesis; nutrition; pregnant; protein expression; receptor; response; vasculogenesis

The goal of this study is to establish the degree to which decreased fetal nutrient availability has duration of exposure and gender-specific affects on the fetal baboon kidney. Significance: The American Kidney Foundation estimates 20 million Americans (1 in 9 adults) suffer from chronic renal disease (CRD); by 2020 the estimate reaches 1 in 4. There are an increasing number of epidemiologic and animal reports that show range of maternal perturbations including maternal nutrient restriction (MNR) in pregnancy that impair fetal renal development, suggesting an in utero component of predisposition to CRD. Preliminary data: Our baboon model at 0.5 of gestation (G) shows that a 30% decrease in maternal global nutrition from 0.16 to 0.5 G (i) decreases proximal tubule density while decreasing mRNA expression of fetal renal extracellular matrix components fibronectin, laminin, collagen IV, integrin-linked kinase, matrix metalloproteinase 2 and TGF/?; (ii) decreases mRNA expression of fetal renal growth factors IGF, VEGF, EGF receptor (R) and PDGFR; and (iii) alters components of the fetal renal renin-angiotensin system (RAS) in a fetal gender-specific manner. Similarities in nutrition, placentation and kidney development between the baboon and humans make this model a unique opportunity for significant primate studies of gene/environment interaction that are not possible in humans. Hypothesis: MNR has duration of exposure and gender specific effects on fetal baboon kidney development that are primarily mediated by decreased extracellular matrix components expression, growth factor expression, cytokine expression and decreased nutrient sensing pathway activity. Reduced fetal nutrient availability [1] decreases nephron length, decreases glomerular endowment and increases glomerular size at term; [2] decreases expression of growth factors involved in vasculogenesis and angiogenesis resulting in decreased peritubular and glomerular capillary density; and [3] impacts the intra- renal renin-angiotensin system in a gender specific manner by increasing intra-renal 11/MHSD1 and aromatase activity. Approach: Studies will be conducted on fresh, frozen and fixed fetal kidney at 0.33, 0.50, 0.66 and 0.90 G using: (i) histology and unbiased stereology; (ii)QRT-PCR/ISH and Western blot/IHC for mRNA and protein expression and localization; (iii) mobility band shift assay for gene transcriptional regulation; and (iv) growth factor activity assay in explants in Matrigel culture and isolated proximal tubule cell 3D culture. Synergy: All three projects study the effects of MNR on the fetal baboon as mediated, at least in part, by the IGF system peptides. Lay Description: We pass more biological milestones before we are born than at any other time in life. Our data will develop what is know about kidney development in the primate and demonstrate that sub-optimal conditions in utero alter the trajectory of renal development. Clinicians will use the information to understand optimal life style and diet in pregnancy.

本研究的目的是确定胎儿营养物质利用率下降的持续时间