We are a collaborative and tightly knit group of investigators who wish to contribute to the CCTRN our expertise in 1) small molecules and stem cells in peripheral arterial disease (John Cooke);2) clinical device development in stem cell delivery, coronary artery disease, and structural heart disease (William Fearon, Robert Robbins, and Alan Yeung);3) multimodality cellular, molecular, and physiologic imaging of stem cells and ischemic cardiovascular diseases (Sanjiv Gambhir, Dwight Nishimura, Joseph Wu, and Phillip Yang);4) bone marrow stem cell harvest and processing (Robert Negrin);and 5) stem cell characterization (Garry Nolan). We propose to contribute a novel multi-modality approach to assess stem cell engraftment employing manganese enhanced MRI (MEMRI) by Phillip Yang, and stem cell localization utilizing lndium-111 cell labeling by Joe Wu and Sam Gambhir. In addition, we will contribute innovative methodology to evaluate tissue perfusion and peri-infarct viability using magnetic resonance imaging (MRI) algorithms developed by Dwight Nishimura and Phillip Yang for peripheral and myocardial imaging, respectively. Finally, we will provide a comprehensive definition of the CD34+ mononuclear cells (MNCs) to be used in our human studies, using the paradigm-changing technology of single cell mass cytometry recently developed at Stanford (Bendall SC et al. Science 2011). This new technology provides a platform for massively multiplexed measurements of single-cell biological parameters that can finely delineate cellular subsets. We intend to correlate these subsets with clinical endpoints in our PAD and CAD research protocols, to determine what cell subsets may be most critical for any observed benefit.
Adult stem cell trials in patients with CAD PAD have shown promise. However, the effect size for most endpoints has been modest. The mechanism(s) of benefit remain poorly understood. We suggest that a better definition and imaging ofthe therapeutic cell population could yield insights that might improve our selection and administration of adult stem cells, and potentially improve therapeutic benefit.
|Schutt, Robert C; Trachtenberg, Barry H; Cooke, John P et al. (2015) Bone marrow characteristics associated with changes in infarct size after STEMI: a biorepository evaluation from the CCTRN TIME trial. Circ Res 116:99-107|
|Cogle, Christopher R; Wise, Elizabeth; Meacham, Amy M et al. (2014) Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes. Circ Res 115:867-74|
|Perin, Emerson C; Murphy, Michael; Cooke, John P et al. (2014) Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells. Am Heart J 168:667-73|
|Bakr, Adel; Pak, Oleg; Taye, Ashraf et al. (2013) Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia. Am J Respir Cell Mol Biol 49:491-500|
|Cooke, John P (2013) Therapeutic transdifferentiation: a novel approach for vascular disease. Circ Res 112:748-50|