Novel Therapeutic Approaches for NPC Disease

项目摘要/摘要 Niemann-Pick病，C1型(NPC1)，是一种常染色体隐性遗传的神经内脏疾病，患者 通常在成年初期死于疾病的并发症。NPC1的临床表型 广泛包括中枢神经系统和外周功能障碍，目前没有FDA- 批准的治疗方法。所附提案旨在开发和理解新的 一类用于改善胆固醇储存和NPC1相关表型的多肽。我们的中心方法 是为了解决NPC1蛋白上游的生化缺陷。首先，我们将了解如何定义 蛋白质和脂肪生物标记物对多肽治疗有反应。第二，我们将进行DMPK研究，并 研究如何通过治疗延长寿命。第三，我们将研究其作用机制。 这些多肽可以减少胆固醇的储存。为推行建议中的计划，我们会利用我们的专业知识 质谱学、生物化学和分子生物学技术。

PROJECT SUMMARY/ABSTRACT Niemann-Pick disease, type C1 (NPC1), is an autosomal recessive, neurovisceral disorder, and patients typically succumb to complications of the disease in the early adulthood years. The clinical phenotype of NPC1 is broad including both central nervous system and peripheral dysfunction and currently there is no FDA- approved therapy. The enclosed proposal seeks to develop and understand the mechanism of action of a new class of peptides to ameliorate cholesterol storage and associated phenotypes of NPC1. Our central approach is to address the biochemical deficits upstream of the NPC1 protein. First, we will understand how defined protein and lipid biomarkers respond to peptide treatment. Second, we will perform a DMPK study and investigate lifespan extension with treatment. Third, we will investigate the mechanism of action by which these peptides reduce cholesterol storage. To carry out the proposed project, we will leverage our expertise in mass spectrometry, biochemistry and molecular biology techniques.