The role of ALK4 signaling in skeletal homeostasis and pathogenesis

ALK4 信号传导在骨骼稳态和发病机制中的作用

• 批准号: 10607071
• 负责人: Vicki Rosen
• 金额: $ 63.66万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607071
• 关键词: Address; Adult; Affect; Affinity; Age; Age Months; Aging; Anemia due to Chronic Disorder; BMP2 gene; Binding; Biological Response Modifier Therapy; Biology; Cells; Chronic; Chronic Disease; Chronic Obstructive Pulmonary Disease; Circulation; Clinical Trials; Complex; Data; Disease; Disease model; Ensure; Event; Exhibits; Extracellular Domain; GDF11 gene; GDF8 gene; Genes; Genetic; Homeostasis; Knowledge; Ligand Binding; Ligands; Minerals; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Osteoblasts; Osteogenesis; Pathogenesis; Pathway interactions; Phenotype; Population; Proteins; Reporting; Repression; Resistance; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Skeleton; Therapeutic; Tissues; Transforming Growth Factor beta; activin A; age related; bone; bone cell; bone fracture repair; bone loss; bone mass; bone repair; bone strength; burden of illness; cancer cachexia; cohort; efficacy evaluation; efficacy testing; member; mouse model; novel; novel therapeutics; obese patients; osteoprogenitor cell; preclinical study; prevent; receptor; response; side effect; skeletal; therapeutic target; transcriptome sequencing

New biologically-based therapeutics that target signaling pathways have tremendous potential to provide novel treatments for chronic and often debilitating diseases. One such approach is the creation of ligand traps, which capture proteins that exhibit high-affinity binding to a receptor extracellular domain, and subsequently prevent these molecules from activating target cells. Preclinical studies employing ligand traps for Acvr2A/B (2A/B-LT), type 2 receptors in the TGF-β superfamily, collectively demonstrate that reducing canonical Smad2/3 signaling reduces the disease burden in mouse models of chronic illnesses. Based on these findings, ongoing and planned clinical trials are evaluating the efficacy of 2A/B-LT in patients with obesity, chronic obstructive pulmonary disease, cancer-induced cachexia, type 2 diabetes, rheumatoid arthritis, and anemia of inflammation. Most of these chronic illnesses also have skeletal manifestations, and beneficial changes in bone mass and strength have been reported in mice treated with 2A/B-LT. However, why 2A/B-LT treatment has positive effects on the skeleton, what cell populations are directly affected by 2A/B-LT, and the mechanism(s) by which decreasing Smad2/3 activation regulates bone cell responses are largely unknown. Filling these gaps in knowledge will be critical to identifying any skeletal side effects of using 2A/B-LT. Findings from our lab suggest that genetic deletion of Alk4, a type 1 receptor within the TGF-β superfamily, in early osteoprogenitors results in increased bone mass in mice. Furthermore, data from our group and others suggests bone homeostasis may be influenced by opposing changes in Smad2/3 and Smad1/5/8 signaling due to shared usage of Acvr2A/B between BMPs and Alk4-activating ligands. We therefore hypothesize that circulating ligands signaling through Alk4 regulate bone homeostasis and pathogenesis by competition between Smad2/3 and Smad1/5/8 signaling. Completion of the aims in our proposal will allow us to identify the bone cell targets of these TGF-β superfamily ligand traps (SA1), determine whether the ligand trap Alk4-FC has therapeutic potential in bone (SA2), examine the efficacy of Alk4-FC in 2 chronic disease models (SA3), and inform about the molecular events that comprise the skeletal response to ligands that activate Smad2/3 signaling (SA4). The questions addressed in this proposal are significant because they fill a critical knowledge gap about potential off- target effects on the skeleton that may occur when 2A/B-LT is used to treat chronic diseases. We believe the results we obtain by completing our studies are impactful because they highlight the potential of using 2A/B-LT and/or Alk4-FC to prevent/modulate the generalized bone loss that occurs with age, as well as to enhance bone fracture repair. Further, our studies will significantly advance our understanding of the role of Smad2/3 and Smad1/5/8 signaling in the adult skeleton, and provide a framework for understanding TGF-β superfamily biology as a mechanism for ensuring homeostasis in bone and other target tissues.

针对信号通路的新的生物疗法具有巨大的潜力 一种治疗慢性且常常使人衰弱的疾病的新方法是创建配体陷阱， 它捕获与受体胞外结构域表现出高亲和力结合的蛋白质，随后 使用 Acvr2A/B 的配体陷阱来防止这些分子激活靶细胞。 (2A/B-LT)，TGF-β 超家族中的 2 型受体，共同证明减少规范的 Smad2/3 基于这些发现，信号传导减轻了慢性疾病小鼠模型的疾病负担。 计划中的临床试验正在评估 2A/B-LT 对肥胖、慢性阻塞性肺疾病患者的疗效 肺部疾病、癌症引起的恶病质、2 型糖尿病、类风湿性关节炎和炎症性贫血。 大多数这些慢性疾病也有骨骼表现，以及骨量和骨量的有益变化。 已报道用 2A/B-LT 治疗的小鼠的强度然而，为什么 2A/B-LT 治疗具有积极作用。 在骨骼上，哪些细胞群直接受到 2A/B-LT 的影响，以及影响的机制 减少 Smad2/3 激活调节骨细胞反应目前尚不清楚。 我们实验室的研究结果表明，知识对于识别使用 2A/B-LT 的任何骨骼副作用至关重要。 早期骨祖细胞中 Alk4（TGF-β 超家族中的 1 型受体）的基因缺失会导致 此外，我们小组和其他人的数据表明骨稳态可能会增加。 由于 Acvr2A/B 的共同使用而受到 Smad2/3 和 Smad1/5/8 信号传导相反变化的影响 因此，我们涵盖了 BMP 和 Alk4 激活配体之间的循环配体信号传导。 通过 Alk4 通过 Smad2/3 和 Smad2/3 之间的竞争来调节骨稳态和发病机制 Smad1/5/8 信号传导的完成将使我们能够确定骨细胞靶点。 这些TGF-β超家族配体陷阱（SA1），确定配体陷阱Alk4-FC是否具有治疗潜力 在骨中 (SA2)，检查 Alk4-FC 在 2 个慢性疾病模型 (SA3) 中的功效，并告知 分子事件，包括骨骼对激活 Smad2/3 信号传导 (SA4) 的配体的反应。 该提案中解决的问题很重要，因为它们填补了关于潜在的关闭的关键知识空白 我们相信，2A/B-LT 用于治疗慢性疾病时可能会对骨骼产生影响。 我们通过完成研究获得的结果具有影响力，因为它们凸显了使用 2A/B-LT 的潜力 和/或 Alk4-FC 以预防/调节随年龄增长而发生的全身骨质流失，以及增强骨质 此外，我们的研究将显着增进我们对 Smad2/3 和骨折修复作用的理解。 成人骨骼中的 Smad1/5/8 信号传导，并为理解 TGF-β 超家族生物学提供框架 作为确保骨骼和其他目标组织稳态的机制。