Epigenetic Modulation of the Epiphyseal Growth Plate to Treat Pediatric Limb Deformities

 描述（由申请人提供）：小儿肢体畸形是临床上具有挑战性的疾病，可导致终身残疾、慢性疼痛，通常需要多次复杂的手术重建来恢复功能。通过改变骨骺生长板的生物景观，可以可逆地减缓或加速四肢生长的治疗策略有可能纠正肢体畸形，同时避免与当前治疗相关的并发症和发病率。 骨骺生长板最初在体内以对称的速率生长，但在发育后期开始显示出基于其在体内的位置的生长速度的变化。我们推测，骨骺生长板的后生状态的变化是负责的差异增长率。MicroRNA是一种非编码RNA小分子，能够通过抑制靶转录因子的活性来介导表观遗传转变。该提案将研究microRNA诱导骺生长板内的表观遗传变化以改变其生长速度以应用于儿科肢体畸形矫正的临床潜力，通过（i）定义与人骺板的手术活检中的生长速度相关的基因调控参数，（ii）验证生长板软骨细胞上的microRNA转录因子调控网络的生物活性，和（iii）评估不同的药物递送策略， 用于治疗肢体长度差异和有角肢体畸形。这项研究的完成将确定小的非编码RNA，可以通过增加或减缓肢体生长来治疗儿童肢体畸形和腿长差异。它还将确定转录因子网络，这些转录因子网络可以在治疗上靶向使用目前在临床实践中用于治疗其他医学病症的药理学试剂来控制lib生长。这项提案还将探讨两种不同的药物输送策略，一种涉及直接注射到骨骺生长板的中心，以均匀增加 或减少整个生长骨骺的生长，以及另一种递送策略，其中治疗剂优先递送到生长骨骺的一侧，以有意地诱导整个生长骨骺的不对称生长，从而可以矫正有角肢体畸形。

 DESCRIPTION (provided by applicant): Pediatric limb deformities are clinically challenging disorders that result in lifelong disability, chronic pain, and often require multiple complex surgical reconstructions to restore function. Therapeutic strategies that can reversibly slow or accelerate the growth of the extremities by altering the biologic landscape of the epiphyseal growth plate have the potential to correct limb deformities while avoiding the complications and morbidity associated with current treatments. Epiphyseal growth plates initially grow at symmetrical rates within the body, but later in development begin to show changes in growth velocity based on their location within the body. We hypothesize that changes in the epigenetic state of the epiphyseal growth plate are responsible for the differential growth rates. MicroRNAs are small non-coding RNA molecules that are capable of mediating epigenetic shift by suppressing the activity of target transcription factors. This proposal will investigate the clinicl potential of microRNAs to induce epigenetic change within the epiphyseal growth plate to alter its growth velocity for applications in pediatric limb deformity correction by (i) defining gene regulatory parameters linked to growth rate in surgical biopsies of the human physis, (ii) validating the biologic activity of microRNA transcription factor regulatory networks on growth plate chondrocytes, and (iii) evaluating different drug delivery strategies that can potentially be used to treat limb length discrepancies and angular limb deformities. Completion of this investigation will identify small non-coding RNAs that can be therapeutically leveraged to treat pediatric limb deformities and leg length discrepancies by increasing or slowing limb growth. It will also identify transcription factor networks that can be therapeutically targeted to control lib growth using pharmacologic agents that are currently being used in clinical practice to treat other medical conditions. This proposal will also explore two different drug delivery strategies, one involving direct injection into the center of the epiphyseal growth plate to uniformly increase or decrease growth throughout the physis, and another delivery strategy where therapeutic agents are delivered preferentially to one side of the physis to intentionally induce asymmetrical growth across the physis, so that angular limb deformities can be corrected.