项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

JUSTINOVA, ZUZANA

项目受资助机构

UNIVERSITY OF PITTSBURGH AT PITTSBURGH

立项年度

2018

立项时间

未公开

项目编号

5R01GM049202-23

研究期限

未知 / 未知

项目级别

国家级

受资助金额

452423.00美元

学科

Behavioral and Social Science; Bioengineering; Chronic Pain; Nanotechnology; Neurodegenerative; Neurosciences; Pain Research; Peripheral Neuropathy;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

XU, YAN

参与机构

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

项目标书摘要：? DESCRIPTION (provided by applicant): This is an amended application seeking continuation of an NIGMS MERIT Award, which has supported a multidisciplinary research program on the studies of mechanisms of general anesthesia and analgesia. In recent years, the research has focused on human glycine receptors (GlyRs) and two bacterial homologues of the pentameric ligand-gated ion channels (pLGICs). High-resolution structural details from the nuclear magnetic resonance and X-ray co-crystallization studies in this project offered mechanistic insights into the role of GlyRs and the related pLGICs in anesthesia and, particularly, in analgesia. In response to a congressional call for the NIH to expand an aggressive basic and clinical research program on the causes and treatments of pain (Section 4305, Patient Protection and Affordable Care Act), this competing renewal will direct a focused research effort towards developing new analgesic therapies in the next funding cycle. A novel strategy based on an unconventional idea for drug discovery is proposed to provide the peripheral nerves with potential analgesic targets through receptor engineering. The central hypothesis is that in certain types of severe and persistent pain, the sensory process of peripheral hypersensitization can be partially controlled by installing non-native chloride (Cl-) channels, thereby creating drug-able modulations of peripheral nociceptors. Two classes of Cl- channels will be developed that will either (a) automatically respond to inflammation-evoked pain by spontaneously mediating Cl- flux in response to changes in tissue pH or (b) serve as exclusive targets for small activating molecules to mediate anti-hyperalgesic actions. Substantive in vitro functional data and in vivo pain behavioral data support the following three specific aims: Specific Aim #1: Evaluate the designed receptors and top drug candidates in vivo and devise the best delivery strategies to target peripheral afferents. Two well-established inflammatory rat pain models will be used to test (1) intraneural and perineural injection and (2) intrathecal injection of expression vectors (including plasmid DNA and peripheral nerve/dorsal root ganglion-targeting rival vectors), and (3) systemic intravenous injection of peripheral-nerve-homing nanoparticles carrying the constructs of the engineered receptors. Systemic immune reaction will be profiled, and strategies to evade immune detection will also be developed. Specific Aim #2: Continue to optimize two classes of Cl- channels as anti-hyperalgesic targets. Class I will be passive channels that will automatically respond to tissue pH changes proportional to the degree of pain-evoking inflammation. Class II will be activatable channels whose agonist or positive allosteric modulator binding sites will be designed and optimized to match non-psychoactive molecules that would otherwise have little or no analgesic action, thereby turning these molecules into long-acting analgesics. Specific Aim #3: Screen and develop non-psychoactive analgesics that act specifically on the optimized Class II channels as exclusive targets. Structure-based in silico screening and in vitro electrophysiology will be combined to search for top candidates. Optimization will be iterated in concert with the receptor designs in Specific Aim #2 and in vivo measurements in Specific Aim #1.