Mechanistic Studies on Meprin Metalloproteases and Meprin-Substrate Interactions in Tissue Injury

Meprin 金属蛋白酶和 Meprin-底物相互作用在组织损伤中的机制研究

• 批准号: 10199258
• 负责人: Elimelda Moige Ongeri
• 金额: $ 30万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199258
• 关键词: Actins; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Area; Award; CCL2 gene; Chronic; Complex; Coupled; Cyclic AMP-Dependent Protein Kinases; Cytoskeletal Proteins; Development; Diabetes Mellitus; Diabetic Nephropathy; Diagnostic; Disease; Disease Progression; E-Cadherin; Early Diagnosis; Endothelial Cells; Enzymes; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Functional disorder; Genes; Genetic Predisposition to Disease; Hypoxia; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury to Kidney; Interleukin-1 beta; Interleukin-18; Interleukin-6; Kidney Diseases; Knockout Mice; Knowledge; Leukocytes; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Meprin; Metabolism; Metalloproteases; Minority Groups; Molecular; Molecular Biology; Neurodegenerative Disorders; Organ; Physiological; Protein Isoforms; Protein Kinase C; Proteins; Proteomics; Proximal Kidney Tubules; Pulmonary Fibrosis; Renal carcinoma; Research; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Single Nucleotide Polymorphism; Skin; Small Intestines; Substrate Interaction; TREM2 gene; Therapeutic; Tight Junctions; Transcend; Underrepresented Minority; biomarker development; brush border membrane; cancer cell; cytokine; diabetic; in vivo; insight; macrophage; monocyte; mouse model; occludin; osteosarcoma; podocyte; precision medicine; programs; response; therapeutic target; tissue injury; tool; translational study; villin

PROJECT SUMMARY/ ABSTRACT. My research program focuses on understanding the cellular and molecular mechanisms underlying the progression of tissue injury mediated by meprin metalloproteases. Meprins comprise of two subunits, α and β, which form two protein isoforms, meprin A (α-α or α-β) and meprin B (β-β) with distinct and overlapping substrates. Meprins are most abundantly expressed in the brush-border membranes of proximal kidney tubules and small intestines. Meprins are also expressed in leukocytes (monocytes and macrophages), podocytes, skin, endothelial cells, and cancer cells. Meprins have been implicated in the pathophysiology of inflammatory- and fibrosis-associated diseases that include kidney disease, inflammatory bowel disease, lung fibrosis, neurodegenerative disease (e.g. Alzheimer’s disease), and cancer. Single nucleotide polymorphisms (SNPs) in the meprin β gene were shown to associate with severity of certain diseases such as diabetic kidney disease and cancer. My research group uses a combination of molecular biology and proteomic approaches to identify meprin substrates and characterize the interactions between meprin isoforms and their substrates. These are coupled with in vivo studies with meprin knockout mouse models to determine how meprin activity impacts the progression of disease. Known meprin substrates include extracellular matrix (ECM) proteins, modulators of inflammation (e.g. proinflammatory cytokines [IL-1β, IL-6, IL-18, MCP-1; and anti-inflammatory proteins Ac-SDKP), cell signaling proteins (e.g. protein kinase A and protein kinase C), mediators of the hypoxia response (e.g. osteosarcoma-9), tight junction proteins (e.g. claudin 5, occludin, E-cadherin, and Z0-1) cytoskeletal proteins (e.g. villin and actin) and proteins that contribute to plaques in AD (e.g. amyloid precursor protein and triggering receptor expressed on myeloid cells 2). The diversity of meprins substrates suggests that complex mechanisms are involved under different conditions and in different organs. It’s important to gain understanding of these mechanisms to facilitate development of diagnostic and therapeutic tools. For the five year period of this proposal, we will conduct studies in three areas; (i) to determine how SNPS in the meprin β gene impact its interactions with substrates and physiological sheddases, (ii) determine how meprin interactions with substrates modulate signaling pathways and impact responses in hypoxia, inflammation, and ECM metabolism, and (iii) to evaluate the use of meprin and meprin cleavage products as biomarkers for development of diagnostic tools for early detection of disease. The proposed research will transcend basic (in vitro and in vivo) to gain insights on the basis for genetic predispositions associated with meprins. Translational studies are also proposed to apply this knowledge in development of diagnostic tools applicable to diabetic kidney injury and Alzheimer’s disease (AD), an important step in advancing precision medicine. Furthermore, this award will facilitate mentoring of trainees from underrepresented minority populations and thus promote diversity of the biomedical workforce.

项目摘要/摘要。我的研究项目集中在理解细胞和