Role of Insulin Receptor-mediated Signaling In Underactive Bladder

胰岛素受体介导的信号传导在膀胱功能低下中的作用

• 批准号: 9805133
• 负责人: weiqun yu
• 金额: $ 26.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805133
• 关键词: Address; Adult; Affect; Animal Model; Animals; Apoptosis; Apoptotic; Biochemical; Bladder; Bladder Control; Bladder Dysfunction; Bladder Tissue; Cell Proliferation; Cell Survival; Complex; Data; Development; Diabetes Mellitus; Distress; Economic Burden; Elderly; Elderly man; Elderly woman; Etiology; Family member; Foundations; Genetic Transcription; Glucose; Growth; Heart failure; Hepatic; Homeostasis; Human; Hyperglycemia; Hyperlipidemia; Immune Response Genes; Incontinence; Insulin; Insulin Receptor; Insulin Resistance; Knock-out; Knockout Mice; Knowledge; LoxP-flanked allele; MYH11 gene; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Morphology; Mus; Muscle Contraction; Muscle function; Muscular Atrophy; Nocturia; Oxygen; Partner in relationship; Pathogenesis; Pathway interactions; Patients; Phenocopy; Phenotype; Pilot Projects; Play; Quality of life; Role; Serum; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Societies; Stress; Symptoms; Tamoxifen; Testing; Therapeutic; Tissues; base; design; diabetic; diabetic patient; disabling symptom; experimental study; glucose metabolism; imaging approach; insight; insulin signaling; lipid metabolism; mRNA Expression; mouse model; muscular structure; novel; novel therapeutics; prevent; promoter; protein expression; receptor-mediated signaling; response; skeletal muscle wasting; urinary

Abstract: Underactive bladder (UAB) or detrusor underactivity (DU) is common in elderly people, and causes distressing storage and voiding symptoms. Treatment options for UAB are extremely limited and generally have poor efficacy. Diabetes mellitus (DM) is well known to cause UAB, however, the underlying molecular mechanism on how DM leads to UAB is not understood. Insulin signaling plays a crucial role in metabolism, and insulin resistance is a key feature in DM. In addition to maintaining metabolic homeostasis, recent progress indicates that insulin signaling is also important for gene transcription, cell proliferation/differentiation, and cell survival, as well. Insulin resistance in different tissues was found to be responsible for hepatic hyperglycemia, cardiac failure, skeletal muscle atrophy, and hyperlipidemia. These activities occur by regulating multiple signaling pathways, including FOXO signaling. However, the role of insulin signaling in bladder tissue is not well studied, and bladder insulin resistance in the pathogenesis of UAB is unknown. Here we are the first to propose that insulin resistance, or disruption of insulin signaling in bladder tissue itself, directly underlies the pathogenesis of diabetic bladder dysfunction (DBD), leading to UAB. To test this hypothesis, we have generated a constitutive heterozygous smooth muscle specific insulin receptor (SMIR+/-) deficient mouse model to mimic the insulin resistance in bladder smooth muscle (BSM). Our preliminary data indicate that SMIR+/- mouse bladder phenocopies DBD/UAB, suggesting a crucial role of insulin resistance in DBD/UAB pathogenesis. In this proposal, we will generate a conditional knockout mouse to specifically delete IR gene in smooth muscle under tamoxifen induction. This model will generate IR signaling deficiency in adult BSM and therefore more closely mimics the human diabetic bladder. We will use this animal model to study its role in the temporal development of DBD/UAB. We will determine: (1) whether IR deletion in BSM contributes significantly to the overall metabolic disorders of the animal by measuring glucose/lipid metabolism, and serum insulin level; (2) whether deficiency of IR mediated signaling in BSM underlies the pathogenesis of DBD/UAB by phenotyping bladder morphology, bladder function, and BSM contractility in these mice. We will further define the potential underlying mechanism in these IR signaling deficiency mice, by studying (1) FoxO family members, (2) FoxO regulated molecules crucial for apoptosis, and (3) molecules critical for smooth muscle structure and function. This study will determine how insulin signaling in BSM impacts its growth, survival, contractility, and the overall bladder function, and provide us with new insights into how insulin resistance leads to DBD/UAB. This knowledge will be important for developing potential novel therapeutic strategies to treat bladder symptoms.!

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