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First-in-class peptide therapeutics for mitochondrial disorders: molecular mechanism of action and optimization of design

线粒体疾病的一流肽疗法：分子作用机制和设计优化

基本信息

批准号：
10727483
负责人：
NATHAN N ALDER
金额：
$ 8.75万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727483
关键词：
Acceleration Administrative Supplement Aging Anisotropy Binding Biological Assay Biological Availability Cells Chronic Complex Connecticut Coupled Data Disease Electronics Equilibrium Equipment Evaluation Failure Financial Hardship Fluorescence Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Frequencies Grant Health Heritability Housing Laboratories Libraries Measurement Membrane Membrane Potentials Mitochondria Mitochondrial Diseases Modeling Molecular Molecular Mechanisms of Action Optics Organelles Pathology Peptides Pharmaceutical Preparations Phase Photons Physiological Power Sources Production Property Protein Import Quality Control Reactive Oxygen Species Reproducibility Research Research Activity Research Support Resolution Sampling Scanning Services Techniques Therapeutic Therapeutic Agents Therapeutic Effect Time Universities Validation Variant Work Xenon amyloid fibril formation cost design experience instrument membrane model mitochondrial dysfunction mitochondrial membrane next generation novel peptide drug physical property productivity loss programs rational design release of sequestered calcium ion into cytoplasm repaired small molecule

项目摘要

SUMMARY This administrative supplement application (PA-20-272) is for the purchase of a single piece of equipment to support the research activities of the NIA grant, “First-in-class peptide therapeutics for mitochondrial disorders: molecular mechanism of action and optimization of design” (R01AG065879). The instrument being sought is a new research grade spectrofluorometer (Fluorolog-QM-75-22-C, HORIBA Scientific). This will replace the existing instrument in my laboratory (Fluorolog 3-22), which experienced a catastrophic failure in September 2022 (in the third year of this R01 project period), rendering the instrument inoperable. This current instrument was purchased in 2008 when I was establishing my laboratory at the University of Connecticut. Although it has consistently yielded high-quality and reproducible data, in recent years the Fluorolog 3-22 has needed major repairs with increasing frequency, on a nearly once-yearly basis. Each major repair costs thousands of dollars and results in extended downtime (typically several weeks) while instrument components are being serviced at the company. Hence, the cost of maintaining this instrument, in terms of financial burden and productivity loss, has become too high to manage. Furthermore, the Fluorolog 3-22 model has now been discontinued by HORIBA and replacement parts (electronics, optics, etc.) are being phased out, meaning that servicing of key instrument components is becoming impossible. The recent instrument failure occurred this month when the xenon arc lamp housing power supply failed. Hence, the only option is to acquire a replacement instrument. Analytical fluorescence spectroscopy is an essential part of my research program and is central to all aims of the grant activities under R01AG065879. These fluorescence-based activities include: (i) analysis of the equilibrium binding properties of peptides and other small molecules with model membranes and mitochondria; (ii) validation, analysis and quality control of novel, rationally designed mitochondria-targeted compounds as therapeutic agents for mitochondrial aging; (iii) assays for the effects of therapeutic compounds on membrane physical properties; (iv) analysis of mitochondrial function and physiological integrity, including membrane potential, calcium flux and reactive oxygen species production; and (v) evaluation of the effects of mitochondrial drugs on protein import and amyloid fibril formation on mitochondrial membranes. These measurements require multiple independent fluorescence techniques (precise emission and excitation spectral scans, anisotropy readings, Forster resonance energy transfer, static and dynamic quenching) and they are done using complex samples that contain model membranes, isolated organelles, and cells. This work therefore requires a top quality spectrofluorometer that can render high-resolution data from samples with complex backgrounds. In this regard, the Fluorolog-QM-75-22-C will be an excellent replacement instrument for steady-state readings. Furthermore, the addition of a Time-Correlated Single Photon Counting (TCSPC) modular add-on, available in new Fluorolog models, will provide fluorescence lifetime measurement capability that will enhance and accelerate this research.

总结