Thrombospondin1 antagonists and diabetic nephropathy

血小板反应蛋白1拮抗剂与糖尿病肾病

• 批准号: 7590423
• 负责人: JOANNE E MURPHY-ULLRICH
• 金额: $ 29.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590423
• 关键词: Ablation; Address; Affect; Amino Acids; Angiotensin II; Animal Model; Antibodies; Attenuated; Binding; Carcinoma; Cell Culture Techniques; Cells; Clinical Research; Complex; Complications of Diabetes Mellitus; Defect; Dermal; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Effectiveness; End stage renal failure; Extracellular Matrix; Fibrosis; Functional disorder; Genetic; Glucose; Goals; Grant; Growth Factor; Histopathology; Homeostasis; Hyperglycemia; Hypertension; Immune; In Vitro; Incidence; Inflammation; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Intraperitoneal Injections; Kidney; Kidney Diseases; Kidney Failure; Leu-Ser-Lys-Leu peptide; Liver Fibrosis; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Myocardial; Pathogenesis; Pathologic; Peptides; Physiological; Production; Protein Precursors; Proteins; Proteinuria; Rattus; Receptor, Angiotensin, Type 1; Regulation; Renal function; Renin-Angiotensin System; Rodent Model; Sclerosis; Signal Transduction; Testing; Therapeutic; Thrombospondin 1; Transforming Growth Factors; United States; Wound Healing; cytokine; diabetic; diabetic cardiomyopathy; glomerulosclerosis; glycemic control; improved; inhibitor/antagonist; intraperitoneal; mortality; mouse model; neutralizing antibody; non-diabetic; novel therapeutics; prevent; protein expression; receptor; treatment strategy; tumor

DESCRIPTION (provided by applicant): Despite increased glycemic control and use of renin-angiotensin system inhibitors, diabetic nephropathy remains a leading cause of end stage renal disease. The fibrogenic cytokine, transforming growth factor-¿ (TGF-¿), is a key molecular factor in the pathogenesis of diabetic nephropathy. The expression of TGF-¿ and its activity are increased in diabetes. TGF-¿ is expressed as a biologically latent molecule that must be converted to its active form in order to induce fibrogenic effects. This activation step represents a major point of regulation of TGF-¿ bioactivity. We identified thrombospondin 1 (TSP1) as the molecular regulator of TGF-¿ activation in diabetes. TSP1 protein expression is increased by mediators of diabetic nephropathy such as glucose and angiotensin II. In vitro studies and a rat model of STZ-induced diabetes with hypertension showed that antagonism of TSP1-dependent TGF-¿ activation by a four amino acid peptide (LSKL) blocked glucose and angiotensin II stimulation of TGF-¿ activity, extracellular matrix production, and prevented and reversed myocardial fibrosis. The LSKL peptide when administered by intraperitoneal injection is an effective antagonist of TGF-¿ -dependent fibrosis in this model and in other non-diabetic models of renal and hepatic fibrosis. The LSKL peptide represents an effective therapeutic strategy for treatment of diabetic nephropathy: this peptide has the unique advantage of selectively inhibiting only the pathogenic increases in TGF-¿ activity due to TSP1-mediated activation. This distinguishes LSKL from other strategies for inhibiting TGF-¿ action, which do not discriminate between homeostatic levels and pathologic excesses of TGF-¿ activity. In these studies, we will test the hypothesis that administration of the LSKL peptide improves renal function and attenuates renal fibrosis by blocking activation of TGF- ¿ in a newly developed genetic mouse model (129/SvEv Ins2 Akita) of type 1 diabetes, which has significant proteinuria and mesangial sclerosis. In Specific Aim 1, mice will receive thrice weekly i.p. injections of LSKL or control (LSAL) peptide over a 15 week period and renal function, morphology, and TGF-¿ signaling will be evaluated. Specific Aim 2 will determine whether a combined therapeutic approach that targets both the angiotensin II type 1 receptor and TSP1 has increased benefit. Importantly, this proposal will address whether homeostatic functions of TGF-¿ are compromised by antagonism of TSP1-dependent activation. Specific Aim 3 will address whether blockade of TSP1-activated TGF-¿ has deleterious effects on homeostatic functions of TGF-¿ with respect to systemic histopathology, tumor incidence, immune cell profile, and dermal wound healing. These studies will help establish the utility of this peptide antagonist of TSP1-dependent TGF-¿ activation as a novel therapeutic for diabetic nephropathy.

描述（由申请人提供）：尽管血糖控制得到加强并使用肾素-血管紧张素系统抑制剂，但糖尿病肾病仍然是终末期肾病的主要原因。 (TGF-¿)，是糖尿病肾病发病机制中的关键分子因子，TGF-¿ TGF-¿ 的活性在糖尿病中增加。表达为生物潜在分子，必须将其转化为活性形式才能诱导纤维形成作用，该激活步骤代表了 TGF-¿我们确定血小板反应蛋白 1 (TSP1) 是 TGF-¿糖尿病肾病介质（如葡萄糖和血管紧张素 II）可增加 TSP1 蛋白的表达。体外研究和 STZ 诱导的糖尿病高血压大鼠模型表明，TSP1 依赖性 TGF-¿四氨基酸肽 (LSKL) 的激活可阻断葡萄糖和血管紧张素 II 对 TGF-¿腹腔注射时，LSKL 肽是 TGF-¿ 的有效拮抗剂。在该模型以及其他肾和肝纤维化的非糖尿病模型中，LSKL 肽代表了治疗糖尿病肾病的有效治疗策略：该肽具有仅选择性抑制 TGF-¿ 致病性增加的独特优势。 TSP1 介导的激活导致的活性，这将 LSKL 与其他抑制 TGF-¿作用，不区分 TGF-¿ 的稳态水平和病理性过量在这些研究中，我们将检验以下假设：施用 LSKL 肽可通过阻断 TGF-¿ 的激活来改善肾功能并减轻肾纤维化。在新开发的 1 型糖尿病基因小鼠模型 (129/SvEv Ins2 Akita) 中，该模型具有显着的蛋白尿和系膜硬化，在特定目标 1 中，小鼠每周接受三次 LSKL 或对照 (LSAL) 肽注射，为期 15 年。周周期与肾功能、形态和 TGF-¿特定目标 2 将评估结合针对血管紧张素 II 1 型受体和 TSP1 的治疗方法是否会增加益处，重要的是，该提案将解决 TGF-¿受到 TSP1 依赖性激活的拮抗作用的影响 具体目标 3 将解决是否阻断 TSP1 激活的 TGF-¿对 TGF-¿ 的稳态功能有有害影响这些研究将有助于确定这种 TSP1 依赖性 TGF-¿ 肽拮抗剂的用途。激活作为糖尿病肾病的新型治疗方法。