Harvard Catalyst Profiles

The overall goal of my lab is to apply principals of pathophysiology of allergic diseases in humans to questions at the bench, and in turn to bring fundamental findings made at the bench back to the clinic. The dominant themes include how lipid mediators and their receptors function in a network to control the development and activation of mast cells, a central cell type in the effector phases of all allergic diseases. We defined the growth factor requirements for the development of human mast cells from their earliest progenitors, and identified a key role for interleukin (IL)-4 as an accessory mitogen. Human mast cells exposed to IL-4 become competent to generate leukotriene C4 (LTC4) the precursor of the powerful bronchoconstrictor LTD4 and the stable metabolite LTE4. This competence is due to the induced expression of LTC4 synthase, the requisite terminal enzyme involved in LTC4 synthesis. These observations explain why mucosal inflammation elicits a mast cell hyperplasia accompanied by strikingly increased regional concentrations of LTC4 LTD4 and LTE4. We discovered that the growth potentiating effect of IL-4 depended on the induction of LTC4S, and the transactivation of the c-kit tyrosine kinase by the type 1 receptor for cys-LTs (CysLT1R). We also demonstrated that CysLT1R on mast cells exists as a heterodimer with the type 2 receptor for cys-LTs (CysLT2R), and that the latter is a potent negative regulator of the former. Most recently, we discovered that LTE4 only a weak agonist of CysLT1R and CysLT2R, is the most potent member of this mediator class for causing chemokine generation by mast cells and potentiating pulmonary inflammation in mice. These actions are due to the purinergic receptor P2Y12, which we have shown to be the long-elusive third cys-LT receptor. We plan to translate these observations into the clinic, and will test the efficacy of a P2Y12 antagonist on clinical reactions to aspirin challenge in aspirin-intolerant asthmatic individuals as a major goal of a U19 funded by NIAID.