Physiologic Roles of Activin and Myostatin Antagonists

激活素和肌生长抑制素拮抗剂的生理作用

• 批准号: 7496482
• 负责人: ALAN L SCHNEYER
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496482
• 关键词: Activins; Adult; Affect; Affinity; Anabolism; BMP15 gene; Binding; Biochemical; Biological; Biological Availability; Birth; Bone Morphogenetic Proteins; Cell Proliferation; Cells; Cessation of life; Characteristics; Child; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Disease; Drug or chemical Tissue Distribution; Estrus; Failure; Family member; Fatty acid glycerol esters; Fertilization; Financial compensation; Follicle Stimulating Hormone; Follistatin; Gametogenesis; Genes; Goals; Growth; Growth Factor; Hepatic; Homeostasis; Hour; Human; Hyperplasia; In Vitro; Individual; Infertility; Insulin; Insulin Resistance; Islets of Langerhans; Knock-in Mouse; Lead; Litter Size; Malignant Neoplasms; Mammals; Mediating; Messenger RNA; Metabolic; Metabolism; Modeling; Mus; Mutant Strains Mice; Neonatal; Numbers; Obesity; Oocytes; Ovarian; Pancreas; Pathway interactions; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Pituitary Gland; Premature Ovarian Failure; Principal Investigator; Protein Isoforms; Proteolysis; RNA Splicing; Range; Rate; Regulation; Reproduction; Research; Role; Signal Transduction; Testing; Tissues; Up-Regulation; Visceral; diabetes mellitus therapy; folliculogenesis; glucose tolerance; hepatic gluconeogenesis; human IRS2 protein; in vivo; insulin sensitivity; intraovarian; islet; mouse model; myostatin; novel; prototype; reproductive; response; size; type I and type II diabetes

DESCRIPTION (provided by applicant): TGFp superfamily growth factors, including activins, myostatin, and bone morphogenetic proteins (BMPs), have numerous roles in development and adults and are often dysregulated in diseases ranging from cancer to infertility. Activin and myostatin are regulated by soluble antagonists, including follistatin (FST) and follistatin like-3 (FSTL3). FST is critical for normal development since FST KO mice die within 24 hours of birth. FSTL3 has many biochemical and functional similarities to FST and a partially overlapping expression pattern, suggesting some degree of compensatory actions. Our preliminary data demonstrate that the, three FST protein isoforms and FSTL3 have different biochemical characteristics that contribute to distinct bioactivities and mechanisms in vitro. To explore the function of the FST isoforms in vivo, we created a knock-in mouse model in which the circulating FST315 isoform was deleted (FST288-only). This mutant mouse developed of a suite of reproductive and metabolic phenotypes, including enlarged pancreatic islets with p-cell hyperplasia, enhanced glucose tolerance and insulin sensitivity, reduced visceral fat, and upregulated hepatic neogenesis. FST288-only mice are also sub fertile and cease ovarian activity prematurely. Our existing FSTL3 KO mouse has many of these same metabolic defects, but distinct reproductive phenotypes. The Broad Goal of this proposal is to determine the mechanisms by which FST315 deletion produces specific reproductive and metabolic alterations. Our overall hypothesis is that FST315 has critical roles in regulating activin, myostatin, and/or BMP actions that are required for normal reproduction and metabolism but are not fulfilled by the FST288 isoform. Specific Aim 1 will elucidate mechanisms where deletion of FST 315 and FST303 leads to activin/BMP mediated subfertility while Aim 2 will examine the role of activin and myostatin in regulating p-cell proliferation, enhanced peripheral insulin sensitivity, and hepatic insulin response. In Specific Aim 3 we will combine these mouse models to determine the degree of functional compensation between FST315/303 and FSTL3 in regulating these important actions of activin and myostatin. Our proposed studies could lead to novel therapies for type 1 and type 2 diabetes and insulin resistance, as well as identify new mechanisms for POF. The number of people diagnosed with obesity and insulin resistance is increasing at an alarming rate, particularly in children, creating a need for new treatments. This research opens a new pathway that could be used to identify new drugs to treat diseases like type I and 2 diabetes and infertility in humans.

描述（由申请人提供）：TGFP超家族生长因子，包括激活素，肌抑素和骨形态发生蛋白（BMP）在发育和成人中具有许多作用，并且在癌症到疾病的疾病中常常失调。激活素和肌生抑素受可溶性拮抗剂的调节，包括卵泡蛋白（FST）和Follistatin oke-3（FSTL3）。 FST对于正常发育至关重要，因为FST KO小鼠在出生后24小时内死亡。 FSTL3与FST具有许多生化和功能相似性，并且表达了部分重叠的表达模式，这表明了一定程度的补偿性作用。我们的初步数据表明，三种FST蛋白同工型和FSTL3具有不同的生化特征，这些特征在体外有助于不同的生物活性和机制。为了探索体内FST同工型的功能，我们创建了一个敲入鼠标模型，其中删除了循环的FST315同工型（仅FST288-仅）。这种突变小鼠由一套生殖和代谢表型，包括具有P细胞增生的胰岛增大，葡萄糖耐受性增强和胰岛素敏感性，内脏脂肪的降低和上调肝新生殖。仅FST288小鼠也是亚肥料，并且过早停止卵巢活动。我们现有的FSTL3 KO小鼠具有许多相同的代谢缺陷，但具有独特的生殖表型。该提案的广泛目标是确定FST315缺失产生特定生殖和代谢改变的机制。我们的总体假设是，FST315在调节正常繁殖和代谢所需的激活素，肌化素和/或BMP动作中具有关键作用，但FST288同工型并未实现。具体的目标1将阐明FST 315和FST303的删除导致激活素/BMP介导的亚植酸的机制，而AIM 2将研究激活素和肌抑素在调节P细胞增殖，增强外周胰岛素敏感性和肝胰岛素反应中的作用。在特定的目标3中，我们将结合这些小鼠模型，以确定FST315/303和FSTL3之间的功能补偿程度，以调节激活素和肌抑素的这些重要作用。我们提出的研究可能导致对1型和2型糖尿病和胰岛素抵抗的新疗法，并确定POF的新机制。被诊断出患有肥胖和胰岛素抵抗的人数正在以惊人的速度增加，尤其是在儿童中，需要新的治疗方法。这项研究开辟了一项新途径，该途径可用于鉴定新药治疗诸如I型和2糖尿病和人类不孕症之类的疾病。