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; 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.

基于生物学的新理论，即目标信号通路具有巨大的潜力 慢性和经常使人衰弱的疾病的新型治疗方法。一种这样的方法是创建配体陷阱， 捕获暴露于受体外细胞结构域的高亲和力结合的蛋白质，然后 防止这些分子激活靶细胞。临床前研究采用ACVR2A/B的配体陷阱 （2a/b-LT），TGF-β超家族中的2型受体，共同证明了减少规范SMAD2/3 信号在慢性疾病的小鼠模型中降低了伯恩的疾病。基于这些发现，正在进行 计划的临床试验正在评估肥胖症患者2A/B-LT的效率 肺部疾病，癌症引起的恶病质，2型糖尿病，类风湿关节炎和炎症贫血。 这些慢性疾病中的大多数也具有骨骼表现，骨骼质量和有益的变化 在用2A/B-LT处理的小鼠中据报道了强度。但是，为什么2a/b-LT治疗具有积极影响 在骨骼上，哪些细胞群体直接受2A/b-LT的影响，以及该机制 降低SMAD2/3激活调节骨细胞反应在很大程度上未知。填补这些空白 知识对于识别使用2A/B-LT的任何骨骼副作用至关重要。我们实验室的发现建议 Alk4的遗传缺失是TGF-β超家族中的1型受体，在早期的骨基因生成剂中导致 小鼠的骨骼质量增加。此外，我们小组和其他人的数据表明骨稳态可能 由于共享ACVR2A/B的使用而受到SMAD2/3和SMAD1/5/8的相对变化的影响 在BMP和ALK4激活配体之间。因此，我们假设循环配体信号传导 通过ALK4调节骨稳态和通过SMAD2/3与 SMAD1/5/8信令。在我们的提案中完成目标将使我们能够确定 这些TGF-β超家族配体陷阱（SA1）确定配体陷阱ALK4-FC是否具有治疗势 在骨（SA2）中，检查ALK4-FC在2种慢性疾病模型（SA3）中的效率，并告知 完成激活SMAD2/3信号传导的配体骨骼反应的分子事件（SA4）。这 该提案中解决的问题很重要，因为它们填补了有关潜在偏离的关键知识差距 - 目标对2A/B-LT用于治疗慢性病时可能发生的骨骼影响。我们相信 我们通过完成研究获得的结果是有影响力的，因为它们强调了使用2A/B-LT的潜力 和/或ALK4-FC，以防止/调节随着年龄的增长的广泛性骨质流失，并增强骨骼 断裂修复。此外，我们的研究将大大提高我们对Smad2/3和 成人骨骼中的SMAD1/5/8信号传导，并提供了理解TGF-β超家族生物学的框架 作为确保骨骼和其他目标时机中稳态的机制。