课题基金 / 基金详情

Mechanism of Prostone Activation During CFTR Modulation

Mechanism of Prostone Activation During CFTR Modulation
CFTR 调节过程中前列酮激活的机制
批准号:
10687435
负责人:
Pamela L. Zeitlin
金额:
$42.68万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-19 至 2024-08-31

项目摘要

项目成果

Pamela L. Zeitlin的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations in the CF transmembrane conductance regulator (CFTR) gene that disrupts the functions of CFTR. Approximately 90% of people with CF have at least one copy of F508del CFTR. F508del CFTR function can be repaired to a significant extent by double and triple combination medications on the market in the USA. The other 10% of people with CF do not have F508del and many of their mutations do not have a medication to restore CFTR. The GOAL of this grant is to explore the efficacy of a new class of CFTR modulator—a prostone—for the ability to activate wild-type and mutant CFTR. Our HYPOTHESIS is that lubiprostone and related prostones activate many forms of CFTR— normal CFTR, F508del CFTR, or other rare mutations, especially those that have been rescued to the cell surface by the marketed modulators. The prostones were developed as chloride channel 2 (CLCN2) activators but interact with receptor-mediated pathways present in airway and gastrointestinal epithelia to boost CFTR- mediated chloride secretion. It is likely that select prostones are dual modulators of both CFTR and CLCN2. CFTR-mediated chloride transport is a meaningful and quantifiable measure to assess efficacy of channel correctors, activators, potentiators, and amplifiers. Correctors, stabilizers, and amplifiers function by increasing CFTR protein levels on the cellular surface, and potentiators increase the open probability of the CFTR channel to increase anion permeability. Current activators that raise cAMP in vitro, forskolin and IBMX, are not clinically safe or available, which means that the double and triple combination modulators on the market are relying on endogenous levels of cAMP. Specific Aim 1: To quantify the effects of lubiprostone and other novel CFTR activators on ion transport in non-CF, F508del CFTR, and non-F508del mutant CFTR-expressing airway epithelial cell cultures. Aim 1A tests the hypothesis that acute lubiprostone stimulates CFTR-mediated chloride transport. Aim 1B tests the hypothesis that chronic exposure to CFTR activators recruits CFTR function and can stimulate CLCN2-mediated chloride secretion. Aim 1C tests the hypothesis that increased CFTR function leads to increased airway surface liquid depth. Specific Aim 2: To study the PGE2 signaling pathway during activation with lubiprostone. The hypothesis is that one or more EP receptor subtypes are target(s) of lubiprostone during activation of chloride secretion by wild-type and mutant CFTR. Aim 2A addresses GPCR coupling from lubiprostone to CFTR and differentiates from lubiprostone activation of CLCN2. Aim 2B tests the hypothesis that EP2 and EP4 receptors are expressed in the same cells as CFTR.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Ph 1-2 Study of Glycerolphenylbutyrate for Cystic Fibrosis IND 125,124 (12/5/15)
  • 批准号:
    9322858
  • 项目类别:
  • 资助金额:
    $12.5万
  • 财政年份:
    2016
  • 负责人:
    Pamela L. Zeitlin
  • 依托单位:
Chloride Channels in Lung Development
  • 批准号:
    7824125
  • 项目类别:
  • 资助金额:
    $6.7万
  • 财政年份:
    2009
  • 负责人:
    Pamela L. Zeitlin
  • 依托单位:
Phase 2 study of digitoxin for cystic fibrosis - IND 70279
  • 批准号:
    7566224
  • 项目类别:
  • 资助金额:
    $23.35万
  • 财政年份:
    2008
  • 负责人:
    Pamela L. Zeitlin
  • 依托单位:
Phase 2 study of digitoxin for cystic fibrosis - IND 70279
  • 批准号:
    7689355
  • 项目类别:
  • 资助金额:
    $22.76万
  • 财政年份:
    2008
  • 负责人:
    Pamela L. Zeitlin
  • 依托单位:
海外基金