SUMMARY Chronic lung disease, including fibrosis, is the fourth leading cause of mortality worldwide. Pulmonary fibrosis (PF) is a debilitating pathology that impedes overall tissue function. A common comorbidity in fibrosis is vasculopathy, characterized by remodeling and loss of microvessels, which substantially worsens prognosis and limits survival, most current therapeutic strategies being largely palliative. The relevance of neovascularization to the pathophysiology of fibrosis has never been resolved as conflicting evidence depicts angiogenesis as both, reparative or pathologic. Therefore, we must begin to understand and model the underlying pathobiology of PVD, alone and with fibrosis, to define cell interactions necessary to maintain normal function and promote repair. We have identified a novel model of vasculopathy dependent on the function of adult pulmonary resident mesenchymal pericyte progenitors (ABCG2pos MPC). The MPC regulate microvascular function during tissue homeostasis and the extent of vasculopathy in lung tissue. Therefore, lung MPC is a previously unstudied target that should be exploited to identify new mechanisms and therapeutic targets relevant to the pathobiology of PVD associated with fibrosis. A premise for this proposal is that that ABCG2pos lung MPC are key constituents of the microvascular niche, as such, disrupted ABCG2pos MPC differentiation accounts in part for the deregulation of microvessel function and remodeling associated with PVD and exacerbation of fibrosis. We hypothesize that ABCG2posMPC regulated loss of microvessel function drives the development of persistent vasculopathy, which exacerbates the onset and development of fibrosis in the lung. In this proposal, we will test that activation of Wnt/?-catenin signaling in MPC exacerbates the onset and persistence of fibrosis in vivo and in vitro. We hypothesize that MPC derived DKK1 modulates MPC-MVEC interactions via regulation of direct cell - cell communication and paracrine effects on MVEC function. We will also test that modulation of DKK1 expression and signaling activity in ABCG2pos MPC will restore microvascular function and attenuate fibrosis. Both in vivo and in vitro we will repurpose drugs currently approved and utilized as chemotherapeutic agents with WT, IPF, PVD MPC & murine models. Successful completion of the proposed studies will define the therapeutic potential for targeting the Dkk1/Lrp6 signaling pathway identified in MPC to restore microvessel function and decrease fibrotic remodeling. We are poised to complete these studies with combined expertise and tools specific to our group.

R01HL136449

2018-02-15

2022-04-30