Development Of Novel Diabetes Therapies Based On Neutralizing FSTL3 Activity

 描述（由申请人提供）：1型和2型糖尿病均涉及产生胰岛素的胰腺β细胞的损失，导致胰岛素分泌不足，无法控制血糖。最终，需要每天注射胰岛素以避免由高血糖引起的一系列病理。虽然含有β细胞的尸体胰岛的移植已经成功地治疗了少数患者，但供应仍然非常有限。从胚胎干细胞产生功能性β细胞仍然是未来治疗的令人兴奋的可能性，但仍将涉及具有免疫保护的移植，除非可以产生患者特异性β细胞。剩余β细胞增殖的诱导在啮齿动物研究中取得了进展，但尚未成功适用于人β细胞。内源性β细胞团的扩增，例如通过β细胞转分化为功能性β细胞，代表了恢复葡萄糖控制的有吸引力的潜在治疗方案。我们先前的研究已经鉴定了激活素信号传导途径及其通过天然拮抗剂FSTL 3的调节对胰岛细胞命运具有影响，使得FSTL 3（FSTL 3 KO小鼠）的损失导致β细胞质量和胰岛大小的扩增，从而改善葡萄糖调节。初步结果表明，这种β细胞扩增至少部分是由于α细胞向β细胞转分化的增加。因此，费尔班克斯制药公司的长期目标是鉴定将复制FSTL 3 KO小鼠的表型并因此具有治疗潜力的FSTL 3拮抗剂。本文提出的研究将通过开发一种新的FSTL 3拮抗剂（具体目标1）以及表征这种拮抗剂与FSTL 3的位点特异性相互作用，从而导致其中和（具体目标2），来解决新糖尿病治疗的临床需求。FSTL 3中和的净效应将是增加的激活素生物活性，这将使用体外生物测定来检测，其中荧光素酶 在激活素信号传导存在下表达增强。这将有助于筛选抑制剂组，以鉴定具有所需特征的候选物，从而获得体内活性的最高可能性。这两个特定目标将共同确定前2至3个候选FSTL 3中和化合物，这些化合物将在体内糖尿病动物模型以及2期应用中的人类胰岛中进行测试。成功的FSTL 3拮抗剂可以在临床试验中测试在3期活动期间治疗人类糖尿病的有效性。最终目标是生产一种新的糖尿病疗法，可以增加患者自身β细胞的数量，从而恢复葡萄糖控制，从而预防糖尿病的发展。

 DESCRIPTION (provided by applicant): Both type 1 and type 2 diabetes involve loss of insulin-producing pancreatic β-cells resulting in inadequate insulin secretion to control blood glucose. Eventually, daily injections of insulin are required to avoid the constellation of pathologies that arise from hyperglycemia. While transplantation of cadaveric pancreatic islets that contain β -cells has been successful for treating a small number of patients the supply is fa too limited. Production of functional β -cells from embryonic stem cells remains an exciting possibility for future treatments but will still involve transplantation with immune protection unless patient-specific β -cells can be produced. Induction of proliferation in remaining β -cell has progressed in rodent studies but has not yet been successfully adapted for human β-cells. Expansion of endogenous β-cell mass, such as through transdifferentiation of β -cells into functional β -cells represent appealing potential therapeutic solutions to restoring glucose control. Our prior research has identified the activin signaling pathway and its regulation by a natural antagonist, FSTL3, as having influence on islet cell fate such that loss of FSTL3 (FSTL3 KO mouse) results in expansion of β -cell mass and islet size, resulting in improved glucose regulation. Preliminary results suggests that this β -cell expansion is due, at least in part, to increased α- to β -cell transdifferentiation. Therefore, the long term goal of Fairbanks Pharmaceuticals is to identify antagonists of FSTL3 that will replicate the phenotype of the FSTL3 KO mouse and thus have therapeutic potential. The research proposed here will address the clinical need for new diabetes therapies by developing a new FSTL3 antagonist (Specific Aim 1) as well as characterizing this antagonist for site-specific interactions with FSTL3 that lead to its neutralization (Specific Aim 2). The net effect of FSTL3 neutralization will be increased activin bioactivity which will be detected using an in vitro bioassay in which luciferase expression is enhanced in the presence of activin signaling. This will facilitate screening panels of inhibitors to identify candidates with the desired characteristics and thus, the highest probability for in vivo activity. Together, the two Specific Aims will identify the top 2 to 3 candidate FSTL3 neutralizing compounds that will be tested in animal models of diabetes in vivo as well as on human islets in a Phase 2 application. Successful FSTL3 antagonists can then be tested in clinical trials for effectiveness in treating diabetes in humans during Phase 3 activitie. The ultimate goal is to produce a new diabetes therapy that can increase the number of a patient's own β -cells that will restore glucose control and thus, prevent development of diabetes.