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）：TGF β超家族生长因子，包括激活素、肌生长抑制素和骨形态发生蛋白（BMP），在发育和成人中具有多种作用，并且在从癌症到不孕症的疾病中经常失调。激活素和肌生长抑制素由可溶性拮抗剂调节，包括卵泡抑素（FST）和卵泡抑素样-3（FSTL 3）。FST对正常发育至关重要，因为FST KO小鼠在出生后24小时内死亡。FSTL 3与FST有许多生化和功能相似之处，并且表达模式部分重叠，这表明了一定程度的代偿作用。我们的初步数据表明，三种FST蛋白亚型和FSTL 3具有不同的生化特性，这些特性有助于不同的体外生物活性和机制。为了探索FST同种型在体内的功能，我们创建了敲入小鼠模型，其中循环FST 315同种型被删除（仅FST 288）。这种突变小鼠发育了一系列生殖和代谢表型，包括胰岛增大伴p细胞增生、葡萄糖耐量和胰岛素敏感性增强、内脏脂肪减少和肝脏新生上调。仅FST 288的小鼠也是低生育力的，并且过早地停止卵巢活动。我们现有的FSTL 3 KO小鼠具有许多相同的代谢缺陷，但具有不同的生殖表型。该提案的主要目标是确定FST 315缺失产生特定生殖和代谢改变的机制。我们的总体假设是，FST 315在调节激活素、肌生长抑制素和/或BMP作用中具有关键作用，这些作用是正常生殖和代谢所需的，但FST 288同种型不能实现。具体目标1将阐明FST 315和FST 303缺失导致激活素/BMP介导的生育力低下的机制，而目标2将检查激活素和肌肉生长抑制素在调节p细胞增殖、增强外周胰岛素敏感性和肝脏胰岛素反应中的作用。在具体目标3中，我们将联合收割机这些小鼠模型，以确定FST 315/303和FSTL 3在调节激活素和肌生长抑制素的这些重要作用中的功能补偿程度。我们提出的研究可能导致1型和2型糖尿病和胰岛素抵抗的新疗法，以及确定POF的新机制。被诊断患有肥胖和胰岛素抵抗的人数正在以惊人的速度增加，特别是在儿童中，这就需要新的治疗方法。这项研究开辟了一条新的途径，可用于识别治疗I型和2型糖尿病以及人类不育症等疾病的新药。