Mechanisms of Neuropeptides Action in Diabetes

神经肽在糖尿病中的作用机制

• 批准号: 8338436
• 负责人: ARISTIDIS VEVES
• 金额: $ 62.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338436
• 关键词: Affect; Amputation; Angiogenic Factor; Animal Model; Animals; Basic Science; Blood Vessels; Cell Count; Cell physiology; Chronic; Collaborations; Data; Development; Diabetes Mellitus; Diabetic Foot; Diabetic mouse; Discipline; Endocrinology; Failure; Fiber; Fibroblasts; Follow-Up Studies; Forearm; Functional disorder; Generations; Growth Factor; Healed; Impaired wound healing; Impairment; Inflammation; Inflammatory; Injury; Intervention; Israel; Lead; Medical center; Molecular; Mus; Neuropathy; Neuropeptides; Nociception; Operative Surgical Procedures; Pain; Patients; Peripheral Nervous System Diseases; Play; Prospective Studies; Research Personnel; Role; Seminal; Severities; Signal Transduction; Skin; Streptozocin; TAC1 gene; Thinking; Tissues; Translating; Translational Research; Ulcer; Vascular Endothelial Growth Factors; Wound Healing; angiogenesis; clinical application; cohort; cytokine; db/db mouse; diabetic; diabetic patient; drug discovery; foot; healing; immunopharmacology; improved; mast cell; mouse model; non-diabetic; novel; novel therapeutic intervention; prospective; protein tyrosine phosphatase 1B; reconstitution; wound

DESCRIPTION (provided by applicant): Peripheral neuropathy plays a major role in the development of diabetic foot ulceration (DFU) because of the pain insensitivity that allows prolonged tissue injury till a chronic wound has been developed. However, recent studies by our unit and elsewhere indicate that the neuropathy-associated lack of locally secreted neuropeptides by the C-nociceptive fibers impair wound healing and this may be of the major reasons that lead to the development of chronic DFU that may necessitate amputation. In the present application we plan to identify the mechanisms through which, the neuropathy-associated lack of neuropeptides and chronic inflammation lead to wound healing failure. Our primary hypothesis is that the lack of neuropeptides in association with the diabetes-induced pro-inflammatory state lead to increased expression and activity of protein tyrosine phosphatase 1B (PTP1B) causing reduced growth factor signaling, reduced fibroblast function and impaired wound healing. In addition, we hypothesize that diabetes-induced PTP1B expression and the neuropathy-related neuropeptide deficiency leads to impaired mast cell function results in deficient secretion of various cytokines and angiogenic factors that reduces angiogenesis and further impairs wound healing. We finally hypothesize that inhibition of PTP1B and mast cell stabilization in diabetic animal models will improve wound healing and lead to the development of new therapeutic approaches. In order to explore our hypothesis, we propose a prospective cohort follow up study in diabetic patients to study the relationship between the severity of neuropathy and neuropeptides expression to PTP1B forefoot and forearm skin expression/activity and mast cell number and activation. We will also examine the association between PTP1B, mast cells and changes in cytokines and growth factors to wound healing impairment. We also propose animal studies that will examine whether interventions that affect these mechanisms can affect the progress of wound healing and can lead to the development of new therapeutic approaches. The proposal has three specific aims: 1.) To explore the hypothesis that the deficiency of neuropeptides in association with the diabetes-induced pro-inflammatory state lead to increased PTP1B expression/activity and mast cell dysfunction are associated with impaired wound healing; 2.) To investigate whether PTP1B inhibition can improve wound healing in diabetes; 3.) To examine whether neuropeptide deficiency causes mast cell dysfunction and contributes to wound healing impairment in diabetes. The application will encompass the collaboration of investigators from the Joslin-Beth Israel Deaconess Foot Center, Vascular Surgery and Endocrinology and the Molecular Immunopharmacology and Drug Discovery Lab at Tufts Medical Center. The collaboration among the various disciplines creates very strong synergy and will lead to novel and clinically useful data and has the potential to create a paradigm shift in the current thinking, lead to seminal discoveries that can be translated to new therapeutic approaches.

描述（由申请人提供）：周围神经病在糖尿病足溃疡（DFU）的发展中起着重要作用，因为疼痛不敏感，允许长时间的组织损伤直到发展为慢性伤口。然而，我们单位和其他地方的最新研究表明，神经病相关的缺乏局部分泌的神经肽是通过C-核纤维损害了伤口愈合的，这可能是导致慢性DFU发展的主要原因，这可能需要截肢。在本应用中，我们计划确定与神经病相关的神经肽缺乏和慢性炎症导致伤口愈合衰竭的机制。我们的主要假设是，缺乏与糖尿病诱导的促炎性状态相关的神经肽导致蛋白质酪氨酸磷酸酶1B（PTP1B）的表达和活性增加，从而导致生长因子信号降低，降低成纤维细胞功能和伤口愈合受损。此外，我们假设糖尿病诱导的PTP1B表达和与神经病相关的神经肽缺乏会导致肥大细胞功能受损导致各种细胞因子和血管生成因子的分泌不足，从而减少血管生成并进一步损害伤口愈合。最终，我们假设抑制PTP1B和糖尿病动物模型中的肥大细胞稳定将改善伤口愈合并导致新的治疗方法的发展。为了探讨我们的假设，我们提出了一项对糖尿病患者的前瞻性队列随访研究，以研究神经病和神经肽表达与PTP1B前脚的严重程度与前脚皮肤表达/活性和肥大细胞的数量和激活之间的关系。我们还将检查PTP1B，肥大细胞与细胞因子和生长因子的变化之间的关联，以伤口愈合障碍。我们还提出了动物研究，该研究将检查影响这些机制的干预措施是否会影响伤口愈合的进展，并可能导致新的治疗方法的发展。该提案具有三个特定的目的：1。）探讨以下假设：与糖尿病诱导的促炎状态相关的神经肽的缺乏会导致PTP1B表达/活性增加和肥大细胞功能障碍与伤口愈合受损有关； 2.）研究PTP1B抑制是否可以改善糖尿病的伤口愈合； 3.）检查神经肽缺乏是否会导致肥大细胞功能障碍并导致糖尿病的伤口愈合障碍。该应用程序将涵盖乔斯林 - 贝丝以色列执事足中心的调查人员，血管外科和内分泌学以及塔夫茨医学中心的分子免疫药理学和药物发现实验室的合作。各个学科之间的合作创造了非常强大的协同作用，并将导致新颖和临床上有用的数据，并有可能在当前思维中产生范式转变，从而导致开创性发现可以转化为新的治疗方法。