Therapeutic Use of mTOT Modulators in Polycystic Kidney Disease

mTOT 调节剂在多囊肾病中的治疗应用

• 批准号: 8832820
• 负责人: Jerry Raymond Colca
• 金额: $ 12.2万
• 依托单位: METABOLIC SOLUTIONS DEVELOPMENT CO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832820
• 关键词: 2,4-thiazolidinedione; Achievement; Address; Adverse effects; Affect; Agonist; Animal Model; Animals; Apoptosis; Applications Grants; Autosomal Dominant Polycystic Kidney; Carbon; Cell Line; Cell Proliferation; Cell model; Cells; Cellular biology; Clinical; Clinical Trials; Complex; Cyst; Cystic kidney; Development; Diabetes Mellitus; Disease Progression; Disease model; Epithelial Cells; Fluids and Secretions; Foundations; Future; Goals; Growth; Hepatic Cyst; Human; Inborn Genetic Diseases; Individual; Inherited; Inner mitochondrial membrane; Insulin; Insulin Resistance; Kidney; Marketing; Metabolic; Mitochondria; Mitochondrial Matrix; Modeling; Mutation; Nephrons; Non-Insulin-Dependent Diabetes Mellitus; Organ; PKD1 gene; PKD2 protein; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phase; Phase II Clinical Trials; Polycystic Kidney Diseases; Process; Program Development; Proliferating; Proteins; Pyruvate; Rattus; Regulation; Research; Research Personnel; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solutions; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Thiazolidinediones; Time; Tissues; Work; autosomal recessive trait; base; cell growth; cell type; experience; human FRAP1 protein; human disease; human subject; mTOR inhibition; novel; novel therapeutics; polycystic kidney disease 1 protein; pre-clinical; protein complex; prototype; public health relevance; receptor

 DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a term applied to a group of inherited disorders characterized by the presence of cysts in the kidney although multiple organs are typically affected. Renal pathologies found in essentially all forms of PKD include increased fluid secretion, matrix remodeling, cellular proliferation, and apoptosis, with a altered differentiation of the epithelial cells lining the renal cysts. PKD represent conditions tht are inherited as either autosomal dominant (AD) or autosomal recessive traits. ADPKD occurs in 1-in-500 to 1-in-1000 individuals, primarily as a result of mutations in one of two genes, PKD1 or PKD2. These mutations drive a pathology which results in inactivation of AMPK and over-activation of mTOR and Wnt signaling pathways leading to inappropriate cellular proliferation of the epithelial cells lining the tubules of the nephron. At this time, there is no therapeutic intervention approved for halting PKD progression. Metabolic Solutions Development Company (MSDC; www.msdrx.com) is developing novel insulin sensitizing agents which interact with a newly identified mitochondrial target (mTOT, mitochondrial Target of the Thiazolidinediones) while sparing activation of the PPAR¿ receptor. These agents have shown efficacy in Phase II clinical trials for type 2 diabetes and modulate carbon flow from pyruvate into the mitochondrial matrix on a tissue specific/metabolic demand basis. Modulation of mTOT by these compounds elicits changes in signaling pathways that include activation of AMPK and inhibition of mTOR and the Wnt signaling pathways in cell and animal models used in the diabetes development program. Since these changes in signaling pathways are in the opposite direction of that seen in PKD, MSDC evaluated the potential therapeutic use of these mTOT modulating insulin sensitizing agents in an animal PKD model and found that they reduced kidney and liver cyst volume. Furthermore, in an initial assessment of the ability of mTOT modulating agents to influence signaling pathways in human cystic epithelial cells derived from ADPKD patients, activation of AMPK was observed. Thus, the overall objective of this Phase I SBIR grant application is to determine which mTOT modulating agent has the potential to be the most effective in human ADPKD therapy. The agent with the best profile for limiting growth of cystic epithelial cells derived from ADPKD patients will be selected for further preclinical development. This future work will be the subject of a Phase II SBIR grant application. The overarching goal of this research effort is to develop a mTOT modulating insulin sensitizing agent for therapeutic intervention in a clinical trial of PKD patients.

 描述（由申请人提供）：多囊肾病（PKD）是一个术语，适用于一组以肾脏中存在囊肿为特征的遗传性疾病，尽管在基本上所有形式的 PKD 中发现的肾脏病理通常都受到影响。液体分泌、基质重塑、细胞增殖和细胞凋亡，以及肾囊肿内衬上皮细胞的分化改变，PKD 代表常染色体显性遗传 (AD) 或遗传性疾病。 ADPKD 发生在 500 分之一到 1000 分之一的个体中，主要是由于 PKD1 或 PKD2 两个基因之一的突变导致的病理结果，导致 AMPK 失活和过度。 mTOR 和 Wnt 信号通路的激活导致肾小管内壁上皮细胞的不适当细胞增殖，目前尚无批准的治疗干预措施。阻止 PKD 进展。代谢解决方案开发公司 (MSDC；www.msdrx.com) 正在开发新型胰岛素增敏剂，其与新确定的线粒体靶标（mTOT，噻唑烷二酮类线粒体靶标）相互作用，同时避免激活 PPAR¿这些药物在 2 型糖尿病的 II 期临床试验中显示出疗效，并根据组织特异性/代谢需求调节从丙酮酸到线粒体基质的碳流。这些化合物对 mTOT 的调节会引起信号通路的变化，包括激活糖尿病发展计划中使用的细胞和动物模型中的 AMPK 和 mTOR 以及 Wnt 信号通路的抑制由于这些信号通路的变化与 PKD 中观察到的方向相反，因此 MSDC 评估了这些信号通路的潜在治疗用途。 mTOT 调节剂在动物 PKD 模型中调节胰岛素增敏剂，发现它们减少了肾脏和肝脏囊肿体积。此外，在对 mTOT 调节剂影响 ADPKD 患者来源的人囊性上皮细胞信号通路的能力的初步评估中，因此，本次 SBIR 资助申请的总体目标是确定哪种 mTOT 调节剂在人类 ADPKD 治疗中最有效。用于限制 ADPKD 患者囊性上皮细胞生长的药物将被选择进行进一步的临床前开发，这项未来的工作将成为 II 期 SBIR 资助申请的主题。用于 PKD 患者临床试验的治疗干预。