THE USE OF FIBRIN HYDROGELS TO PROMOTE SALIVARY GLAND REGENERATION

摘要 根据美国癌症协会的数据，今年将有超过6万人患上头颈癌 每年，这些患者必须接受放射治疗才能存活。这种疗法通常会破坏唾液。 腺体(SG)，导致典型的永久性分泌功能丧失。目前的治疗方法仍然是 很大程度上无效，治疗干预措施仅限于使用适量唾液替代品 有效性和只能提供暂时缓解的药物。考虑到高度的需求和 由于目前治疗方法的局限性，开发替代疗法以恢复SG的功能是至关重要的。在……里面 为了应对上述挑战，我们建议引入FGF7和FGF10，这两种产品都激活了 促进SG上皮形态发生和分化的FGF2b信号(目标1和2，体外和体内， )。在加固了我们的支架以促进SG的形态形成和分化后，我们将 然而，仍然面临缺乏或发育不良的血管和神经系统，如以下所示 反复研究表明，照射后的SG失去了血管形成和神经支配。在回应这些问题时 挑战，我们将借鉴我们之前的发现，表明血管内皮生长因子和纤维生长因子9有助于血管形成和 促进神经支配的神经营养因子(如神经生长因子)(目标3)。我们假设一种改装的FH支架 含有固定化L1多肽(L1p)和GF(L1p-GF-FH)将促进功能组织的形成 照射后的SG。目的1：在体外使用加固支架显示持续的分泌功能。我们会 确定将Fgf7和FGF10掺入L1p-FH(称为EP-FH)支架是否允许分泌 在受照射的SG中保持较长时间完好无损的功能。目标2：将表现出持续的分泌性 在体内使用加固的脚手架发挥作用。我们将决定是否将FGF7和FGF10纳入 L1P-FH(称为EP-FH)支架使分泌功能在较长时间内保持不变 照射后SMG小鼠模型。目标3：在活体内恢复受照射的SG的全部功能。我们将把我们的 含聚合物微粒的EP-FH支架暂时释放促血管生成和促神经支配的生长因子 模拟体内生理的序列，促进放射后SMG的功能恢复 治疗。综上所述，我们建议的研究将扩展我们迄今使用L1P恢复SG功能的发现， 从而允许更大的可持续性和更深程度的功能性。

ABSTRACT According to the American Cancer Society, more than 60,000 people will develop head and neck cancer this year and those patients must receive radiation therapy to survive. This treatment regularly destroys the salivary glands (SG), leading to a loss of secretory function which is typically permanent. Current treatments remain largely ineffective, with therapeutic interventions being limited to use of saliva substitutes with modest effectiveness and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore SG functioning is essential. In response to the challenges noted above, we propose introduction of FGF7 and FGF10, both of which activate FGF2b signaling to promote SG epithelial morphogenesis and differentiation (Aims 1 and 2, in vitro and in vivo, respectively). Having fortified our scaffold to enhance SG morphogenesis and differentiation, we will nonetheless still be faced with absent or poorly developed vasculature and nerve systems, as indicated by repeated studies demonstrating loss of vascularization and innervation in irradiated SG. In response to these challenges, we will draw on our previous findings indicating VEGF and FGF9 to aid vascular formation and neurotrophic factors (e.g., NGF) to promote innervation (Aim 3). We hypothesize that a modified FH scaffold containing immobilized L1 peptides (L1p) and GF (L1p-GF-FH) will promote formation of functional tissue in irradiated SG. Aim 1: will demonstrate sustained secretory function using a fortified scaffold in vitro. We will determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in irradiated SG. Aim 2: will demonstrate sustained secretory function using a fortified scaffold in vivo. We will determine whether incorporation of FGF7 and FGF10 into the L1p-FH (termed Ep-FH) scaffold allows secretory function to remain intact for an extended duration in an irradiated SMG mouse model. Aim 3: will restore full functionality to irradiated SG in vivo. We will combine our Ep-FH scaffold with polymeric microparticles to release pro-angiogenic and pro-innervation GF in a temporal sequence, mimicking the in vivo physiology, to enhance functional recovery of SMG following radiation treatment. In summary, our proposed studies will extend our findings to date using L1p to restore SG function, thereby allowing for both greater sustainability and a deeper degree of functionality.