Life Sciences & Biotechnology
Title : | Understanding arterial wall fibrosis in Takayasu arteritis: role of circulating T helper lymphocytes in driving the activation of TGF-beta mediated pathways in aortic adventitial fibroblasts and its potential for therapeutic modulation |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Durga Prasanna Misra, sanjay Gandhi Postgraduate Institute Of Medical sciences, Uttar Pradesh |
Timeline Start Year : | 2024 |
Timeline End Year : | 2027 |
Contact info : | durgapmisra@gmail.com |
Details
Executive Summary : | Arterial wall fibrosis, a common feature of Takayasu arteritis (TAK), leads to arterial narrowing and stroke or myocardial infarction. The study aims to evaluate the role of the Notch-1-mTORC1 pathway in driving Th17 lymphocyte differentiation in TAK, up-regulate fibrotic pathways in human aortic adventitial fibroblasts (HAoAF), and therapeutically modulate the cross-talk between TAK and HAoAF using immunosuppressive drugs, anti-fibrotic drugs, or a combination of immunosuppressive and anti-fibrotic drugs. The hypothesis is that Notch-1-mTORC1 activation drives differentiation of PD1+ CD4+ T helper and PD1+Th17 lymphocytes, which secrete TGF-β1, which in turn activates HAoAF. Targeting CD4+ T helper/ PD1+Th17 lymphocytes and HAoAF cross-talk might reduce arterial wall fibrosis in TAK. Experiments involve cultured CD4+ T helper lymphocytes from TAK and healthy controls, and gene expression profiles, expression of collagen I and III, alpha-smooth muscle actin (AsMA), and activation of TGF-β1-mediated canonical and non-canonical pathways. In vitro therapeutic modulation of TAK CD4+ T helper lymphocytes and HAoAF interaction with mTORC1 inhibitor sirolimus, TGF-β1-inhibitor tadalafil, antifibrotics nintedanib and pirfenidone, combination of sirolimus and tadalafil, IL-17 inhibitor secukinumab, and secukinumab with tadalafil will be studied. The study suggests that targeting T lymphocyte-HAoAF cross-talk to ameliorate arterial wall fibrosis in TAK may offer a new treatment strategy to reverse arterial narrowing through repurposing available drugs. If this effectively reduces arterial fibrosis, it could be explored in other diseases where both CD4+ T lymphocytes and fibroblast activation play a role. |
Co-PI: | Prof. Vikas Agarwal, sanjay Gandhi Postgraduate Institute Of Medical sciences, Lucknow, Uttar Pradesh-226014 |
Total Budget (INR): | 49,63,920 |
Organizations involved