A therapy for improving diabetic ulcer healing

改善糖尿病溃疡愈合的疗法

• 批准号: 10820107
• 负责人: SHEAU-YU Teddy HSU
• 金额: $ 33.53万
• 依托单位: ADEPTHERA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10820107
• 关键词: Acceleration; Acromegaly; Adverse effects; Affect; Agonist; American; Amputation; Animals; Blood Circulation; Blood Vessels; Blood flow; Chronic; Circulation; Complex; Complications of Diabetes Mellitus; Debridement; Dermal; Developed Countries; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Disease model; Endothelium; Epithelium; Etiology; Exudate; FDA approved; Face; Family; Foot Ulcer; Formulation; Functional disorder; Gel; Half-Life; Hormones; Human; Hyperglycemia; Immune response; Impairment; In Situ; Infection; Injections; Limb structure; Lower Extremity; Lymphangiogenesis; Measures; Mediating; Melanocyte stimulating hormone; Modeling; Morbidity - disease rate; Mus; Nerve; Neuroendocrine Tumors; Patients; Peptide Signal Sequences; Peptides; Peripheral Nervous System Diseases; Persons; Pharmacotherapy; Play; Prevalence; RAMP1; Recurrence; Regulation; Risk Factors; Rodent; Role; Series; Signaling Protein; Site; Somatostatin Receptor; Sterile coverings; Streptozocin; Therapeutic Uses; Tissues; Treatment Cost; Vascular Permeabilities; Vascularization; Vasodilation; absorption; adrenomedullin; analog; angiogenesis; calcitonin receptor-like receptor; chronic ulcer; chronic wound; cost; cost estimate; db/db mouse; diabetes management; diabetic; diabetic ulcer; drug candidate; endothelial dysfunction; healing; hemodynamics; hormone therapy; immune function; improved; in vivo; ischemic injury; limb amputation; monomer; mortality; nanomedicine; neurotransmission; non-healing wounds; novel; novel therapeutics; peptide drug; pressure; prevent; receptor; receptor-activity-modifying protein; self assembly; stem; stem cells; subcutaneous; tissue regeneration; vasculogenesis; wound; wound bed; wound closure; wound environment; wound healing

Diabetic ulcer is one of the major complications of diabetes mellitus because of poor management of hyperglycemia. The prevalence of diabetic ulcer ranges from 14 to 24% among diabetes patients. In the U.S., diabetic ulcer affects over 900,000 peoples a year, and leads to >80,000 limb amputations annually. It was estimated that the management of diabetic ulcers represents over one third of the total cost of treatment of diabetes complications in developed countries. Current management of diabetic ulcers mainly focuses on the elimination of infection, the use of dressings to maintain a moist wound bed, offloading high pressure in the extremities, and debridement to improve healing. Although these measures have improved the survival of patients, there is a lack of pharmacotherapy that can substantially improve the healing of chronic wounds in diabetes patients. Clearly, novel therapeutics that can improve wound healing and prevent the recurrence of chronic ulcers in diabetes are much needed. Recent advance has shown that adrenomedullin family peptides play crucial roles in the regulation of vasculogenesis and immune response, and can protect against diabetes- associated etiology. These peptides have also been shown to accelerate wound healing, perhaps by improving angiogenesis, immune response, vascular permeability, and tissue regeneration in wound sites. Because these peptides have poor stability in vivo, they are poor drug candidates. To overcome this obstacle, we have developed a series of super-agonistic analogs that self-assemble to form gels in situ and slowly release the monomeric analog in vivo. Based on this discovery, we propose to develop an analog gel therapy for accelerating wound healing in diabetes patients by improving re-epithelialization, granulation, blood flow, and revascularization within the wound environment. In the proposed study, we will (1) identify an optimal gel formulation that provides sustained and localized treatment in vivo and (2) investigate the efficacy of the selected analog gel on wound healing in two rodent diabetic ulcer models. Successful development of this novel hormonal therapy has the potential to significantly reduce the mortality and morbidity resulting from nonhealing foot ulcers among diabetes patients.

糖尿病溃疡是糖尿病的主要并发症之一， 高血糖症糖尿病溃疡的患病率在糖尿病患者中为14%至24%。在美国， 糖尿病溃疡每年影响90多万人，每年导致超过80 000人截肢。这是 据估计，糖尿病溃疡的管理占糖尿病治疗总费用的三分之一以上。 糖尿病并发症在发达国家。目前糖尿病溃疡的管理主要集中在 消除感染，使用敷料保持伤口床湿润， 四肢和清创术以改善愈合。虽然这些措施改善了 对于患者，缺乏可以显著改善慢性伤口愈合的药物治疗， 糖尿病患者。显然，可以改善伤口愈合并防止复发的新疗法是可行的。 糖尿病的慢性溃疡是非常需要的。最近的研究表明，肾上腺髓质素家族肽 在调节血管生成和免疫反应方面起着至关重要的作用，并可预防糖尿病- 相关病因。这些肽还被证明可以加速伤口愈合，也许是通过改善 血管生成、免疫反应、血管渗透性和伤口部位的组织再生。因为 这些肽在体内的稳定性差，它们是差的候选药物。为了克服这一障碍，我们必须 开发了一系列超级激动剂类似物，这些类似物在原位自组装形成凝胶，并缓慢释放药物。 体内的单体类似物。基于这一发现，我们建议开发一种类似的凝胶疗法， 通过改善上皮再生、肉芽形成、血流加速糖尿病患者的伤口愈合， 伤口环境内的血运重建。在拟议的研究中，我们将（1）确定最佳凝胶 提供体内持续和局部治疗的制剂和（2）研究所述制剂的功效。 选择的模拟凝胶对两种啮齿动物糖尿病溃疡模型中伤口愈合的影响。成功开发这 新的激素疗法有可能显著降低由以下原因引起的死亡率和发病率： 糖尿病患者的足部溃疡不愈合。