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Targeting T2 inflammation-evoked mechanical endotypes of ASM shortening in asthma

US · IL NIH grant awarded #nih-5R01HL164404-03

Summary

This research project aims to understand the molecular mechanisms behind enhanced human airway smooth muscle (HASM) shortening in asthma, specifically focusing on type 2 (T2) inflammation and bitter taste receptors (TAS2Rs), to develop novel bronchodilators and treatment strategies.

What they want

The project seeks to gain foundational knowledge on the mechanical endotypes of HASM shortening in asthma (inflammation-dependent and -independent) and identify improved bronchodilators. It will characterize T2- and non-T2-mediated molecular kinetics and mechanics of excitation-contraction (E-C) coupling in HASM shortening. Additionally, it will determine the microRNA-epigenetic nexus by which TAS2R activation promotes the functional efficacy of β2-adrenoceptors (β2ARs) and inhibits the mechanical endotypes of HASM shortening in asthma. This will involve leveraging single-molecule and single-cell micromechanical methods, and integrative genetics and genomics approaches in clinically relevant human precision cut lung slices (hPCLS) and primary HASM cells.
Deliverables
  • New knowledge on inflammation-dependent and -independent regulation of E-C coupling in HASM shortening
  • Uncover previously unidentified TAS2R paradigms to mitigate the physiological loss of β2AR function
  • Establish new druggable targets and agents to treat β2-agonist-insensitivity in asthma
Technical requirements
  • Single-molecule micromechanical methods
  • Single-cell micromechanical methods
  • Integrative genetics approaches
  • Integrative genomics approaches
  • Use of human precision cut lung slices (hPCLS)
  • Use of primary HASM cells derived from donor lungs of patients with and without severe asthma
  • Focus on bitter taste receptors (TAS2Rs)
  • Focus on polycomb group (PcG) protein EZH2 (enhancer of zeste homolog 2)
  • Focus on microRNA-214 (miR-214)
  • Focus on β2-adrenoceptor (β2AR)

Market context

inferred from NAICS
Professional, Scientific & Technical Services
NAICS 541714
US market size
$2.0T
Typical award
$25K – $50M
Typical buyers
All federal civilianDoDStates
Commonly required
8(a)WOSBSDVOSBPE/PMP

Sector-level estimate — full code lookup not yet in catalog.

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