Physiologic Roles of Activin and Myostatin Antagonists

描述(申请人提供)：TGFp超家族生长因子，包括激活素、肌肉生长抑素和骨形态发生蛋白(BMPs)，在发育和成人中具有多种作用，通常在从癌症到不孕不育的疾病中调节失调。激活素和肌肉生长抑素受可溶性拮抗剂的调节，包括卵泡抑素(FST)和卵泡抑素样蛋白-3(FSTL3)。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。FSTL3在生化和功能上与FST有许多相似之处，并且表达模式部分重叠，表明FSTL3具有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FSTL3具有不同的生化特性，从而在体外具有不同的生物活性和机制。为了探索FST亚型在体内的功能，我们建立了一个敲入小鼠模型，在该模型中循环中的FST315亚型被删除(仅FST288)。该突变小鼠发育出一系列生殖和代谢表型，包括胰岛肥大伴p细胞增生，糖耐量和胰岛素敏感性增强，内脏脂肪减少，肝脏新生增加。仅携带FST288基因的小鼠也处于亚生育状态，并会过早停止卵巢活动。我们现有的FSTL3 KO小鼠具有许多相同的代谢缺陷，但具有不同的生殖表型。这项提案的广泛目标是确定FST315缺失导致特定生殖和代谢变化的机制。我们的总体假设是，FST315在调节激活素、肌肉生长抑素和/或骨形态发生蛋白的作用中起关键作用，这些作用是正常生殖和新陈代谢所必需的，但不是由FST288亚型完成的。特定的目标1将阐明FST315和FST303缺失导致激活素/骨形态发生蛋白介导的不育的机制，而目标2将研究激活素和肌肉生长抑素在调节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，我们将结合这些小鼠模型来确定FST315/303和FSTL3在调节激活素和肌肉生长抑素这些重要作用方面的功能代偿程度。我们提出的研究可能导致治疗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。被诊断为肥胖和胰岛素抵抗的人数正在以惊人的速度增长，特别是在儿童中，这产生了对新治疗方法的需求。这项研究开辟了一条新的途径，可以用来确定治疗人类I型和II型糖尿病和不孕不育等疾病的新药。

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.