This proposal describes a 5-year training program for the development of an academic research career in Pulmonary Medicine. The principal investigator has completed three years of cell physiology training as a clinician investigator and Glaxo Research Grant Awardee and subsequently two further years of training at UCSF in molecular and vascular cell biology, as a Mayo Foundation Scholar. This KO8 program will support investigations into the role of alpha9-beta1 integrin and vascular endothelial growth factors (VEGF) C and D in pulmonary lymphatic development and function. The principal investigator will be supported and mentored in these endeavours by Dr Debobrata Mukhopadhyay, a leader in VEGF and VEGF receptor biology and Dr Dean Sheppard, an international expert in integrin biology. In addition, an advisory committee of accomplished and well-established scientists will regularly provide the principal investigator with scientific and career advice. Homozygous inactivation of the integrin alpha9 subunit in mice is uniformly lethal by postnatal day 12 as a result of bilateral chylothoraces and respiratory failure. Recent work by the principal investigator has shown that VEGF-C and D directly bind the integrin alpha9-beta1 to transduce cell adhesion and migration suggesting that the co-ordinated function of these proteins is required for normal lymphatic development and function. The proposed experiments will therefore address the following specific aims: 1) To determine the molecular characteristics of the binding interaction of VEGF-C/D to alpha9beta1, 2) To determine the interaction of VEGF-C/D, alpha9beta1 and VEGF-R3 and subsequent intracellualr signalling that transduces lymphangiogenic endothelial cell functions such as proliferation, and 3) To determine if VEGF-C and/or D induced lymphangiogenesis in vivo is alpha9beta1 integrin dependent. The Thoracic Disease Research Unit at the Mayo Clinic provides an ideal environment to ensure completion of all the proposed experiments and tuition in the principles of molecular and vascular cell biology. In addition, this environment will provide a dedication and enthusiasm toward scientific mentoring and career development that will ensure the principal investigator achieves his goal of becoming an independent investigator in academic Pulmonary Medicine. To date the biology of the lymphatic system has largely been ignored, however recently it has become clear this has been a mistake since human diseases such as lymphedema are clearly associated with genetic abnormalities of the VEGF control system for the lymphatic vessels. By addressing the Specific Aims of this proposal the poorly understood and appreciated biology of pulmonary lymphatics will be more clearly defined, in the context of developing novel pharmacotherpeutic targets for treatment or prevention of pulmonary diseases such as lung edema, wound healing and cancer metastases.
| Gupta, S K; Oommen, S; Aubry, M-C et al. (2013) Integrin ýý9ýý1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition. Oncogene 32:141-50 |
| Oommen, Saji; Gupta, Shiv K; Vlahakis, Nicholas E (2011) Vascular endothelial growth factor A (VEGF-A) induces endothelial and cancer cell migration through direct binding to integrin {alpha}9{beta}1: identification of a specific {alpha}9{beta}1 binding site. J Biol Chem 286:1083-92 |
| Gupta, Shiv K; Vlahakis, Nicholas E (2010) Integrin alpha9beta1: Unique signaling pathways reveal diverse biological roles. Cell Adh Migr 4:194-8 |
| Gupta, Shiv K; Vlahakis, Nicholas E (2009) Integrin alpha9beta1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase. J Cell Sci 122:2043-54 |
