Lipase Maturation Factor 1 in Hypertriglyceridemia

高甘油三酯血症中的脂肪酶成熟因子 1

• 批准号: 10203561
• 负责人: MIKLOS PETERFY
• 金额: $ 42.3万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10203561
• 关键词: Address; Adult; Animal Model; Biological Assay; Blood Vessels; Calnexin; Catabolism; Cell physiology; Client; Clinical; Clinical Trials; Complex; Development; Disease; Dyslipidemias; Endoplasmic Reticulum; Energy Metabolism; Enzymes; Exhibits; Family; Genes; Genetic; Genetic study; Glycoproteins; Hepatosplenomegaly; Homeostasis; Human; Hyperlipoproteinemia; Hypertriglyceridemia; Impairment; Knock-out; Knockout Mice; Knowledge; Lead; Lectin; Lipase; Lipids; Lipoproteins; Mediating; Metabolic; Modality; Modeling; Molecular Chaperones; Mus; Mutation; Neonatal; Patients; Pharmaceutical Preparations; Plasma; Population Control; Proteins; Role; Syndrome; Testing; Therapeutic; Treatment Efficacy; Variant; Xanthomas; acute pancreatitis; adeno-associated viral vector; base; carbohydrate metabolism; cardiovascular disorder risk; effective therapy; gene replacement; gene therapy; hepatic lipase; improved; in vivo; lipoprotein lipase; loss of function; metabolic phenotype; mouse model; novel; novel therapeutic intervention; polypeptide; protein degradation; recombinase-mediated cassette exchange; reconstitution; small hairpin RNA; therapeutic evaluation; therapeutic gene; virtual

Primary hypertriglyceridemia (HTG) is a common clinical presentation of dyslipidemia characterized by abnormally elevated plasma TG level. HTG is associated with increased risk of cardiovascular disease and, in its severe manifestations, acute pancreatitis, eruptive xanthomas, lipemia retinalis and hepatosplenomegaly. The genetic basis of HTG is heterogeneous and includes monogenic and polygenic forms. Monogenic HTG (mHTG), also known as type 1 hyperlipoproteinemia and familial chylomicronemia syndrome, represents a rare and severe form of the condition and is caused by homozygous mutations in genes related to the catabolism of TG-rich lipoproteins. Polygenic HTG (pHTG) is more prevalent and thought to result from the cumulative effects of heterozygous variants in multiple genes, including those involved in mHTG. We identified mutations Lipase Maturation Factor 1 (LMF1) as a rare cause of mHTG. While LMF1 has been characterized as a lipase-chaprone involved in the folding of LPL and HL, a more general role in ER homeostasis is emerging. However, the in vivo correlates of LMF1 function remain poorly understood due to the lack of a viable animal model of LMF1 deficiency. In Aim 1a, we will address this knowledge gap through the development and characterization of conditional Lmf1-knockout (cLmf1-KO) mice. Effective management of HTG in LMF1-deficient patients remains an major unmet clinical need, because traditional lipid-lowering medications are largely ineffective Gene-based therapies including LPL gene-replacement and APOC3-suppression represent promising opportunities in mHTG. However, as virtually all mHTG patients in clinical trials harbor LPL mutations, the evaluation of therapeutic efficacy in LMF1-deficient patients is challenging. In Aim 1b, we will use cLmf1-KO mice to evaluate the potential benefits of gene-based therapeutic approaches in LMF1 deficiency. While the role of LMF1 in mHTG is well established, our preliminary results suggest that heterozygous LMF1 variants may also contribute to pHTG. In Aim 2, we will test this hypothesis by evaluating the functional impact of pHTG-associated LMF1 variants on LPL maturation and assessing the genetic burden they confer to the LMF1 gene. In conclusion, the proposed studies will lead to a better understanding of the role of LMF1 in monogenic and polygenic HTG and provide proof-of-principle for novel therapeutic approaches in LMF1 deficiency.

原发性高甘油三酯血症（HTG）是一种常见的临床表现，以血浆甘油三酯水平异常升高为特征。HTG与心血管疾病的风险增加相关，并且在其严重表现中，与急性胰腺炎、发疹性黄瘤、视网膜脂血症和肝脾肿大相关。HTG的遗传基础是异质的，包括单基因和多基因形式。单基因HTG（mHTG），也称为1型高脂蛋白血症和家族性乳糜微粒血症综合征，是一种罕见而严重的疾病，是由与富含TG的脂蛋白的催化剂相关的基因纯合突变引起的。多基因HTG（pHTG）更为普遍，被认为是由多个基因（包括mHTG相关基因）中杂合变体的累积效应所致。我们发现脂肪酶成熟因子1（LMF 1）突变是mHTG的罕见原因。虽然LMF 1已被表征为参与LPL和HL折叠的脂肪酶-chaprone，但在ER稳态中的更普遍作用正在出现。然而，在体内相关的LMF 1功能仍然知之甚少，由于缺乏一个可行的动物模型LMF 1缺陷。在目标1a中，我们将通过条件性Lmf 1基因敲除（cLmf 1-KO）小鼠的开发和表征来解决这一知识缺口。LMF 1缺陷患者的HTG的有效管理仍然是一个主要的未满足的临床需求，因为传统的降脂药物在很大程度上是无效的，基于基因的治疗，包括LPL基因替代和APOC 3抑制代表了mHTG的有希望的机会。然而，由于临床试验中几乎所有的mHTG患者都携带LPL突变，因此LMF 1缺陷患者的疗效评价具有挑战性。在目标1b中，我们将使用cLmf 1-KO小鼠来评估基于基因的治疗方法在LMF 1缺陷中的潜在益处。虽然LMF 1在mHTG中的作用已经得到了很好的证实，但我们的初步结果表明，杂合LMF 1变体也可能导致pHTG。在目标2中，我们将通过评估pHTG相关LMF 1变体对LPL成熟的功能影响和评估它们赋予LMF 1基因的遗传负担来验证这一假设。总之，拟议的研究将导致更好地了解LMF 1在单基因和多基因HTG中的作用，并为LMF 1缺乏症的新治疗方法提供原理证明。