Dr. Reilly has a track record in mechanistic patient oriented research (POR) and mentorship at the University of Pennsylvania (Penn). His Cardiometabolic Research Program is dedicated to human translational and genomic studies of cardiometabolic diseases (CMD). His program is based in Penn's Cardiovascular (CVI) and Translational (ITMAT) Institutes and is highly integrated into the training missions sponsored by Penn's Clinical and Translational Science Award (CTSA). This provides an outstanding environment for translational POR and for mentoring K24 trainees. He has had a track record of continuous NIH funding, mentorship of multiple physician scientists in translational POR, and numerous high-impact publications led by multiple K24 trainees, several of whom have established their own independent POR careers. Dr Reilly is committed to training young clinical investigators in cutting-edge translational technologies and mentoring them to independent careers in POR. With current K24 support, he has been successful in mentoring a new generation of POR researchers (thirty K24 trainees) and in expanding his own POR in CMD (PI for 3 R01, one U01). In this K24 renewal, he proposes to (1) augment his scientific and mentoring skills and devote more time to mechanistic POR, (2) focus on mentoring new clinical investigators in mechanistic POR, and (3) pursue innovative POR in a unique training environment for mentoring young clinical investigators to independent careers in POR. Macrophages represent a critical cell type at the intersection of many CMDs. Reilly's group has developed a method for differentiating human induced pluripotent stem cells (hiPSC) to macrophages (IPS-DM), a powerful system for macrophages functional genomics. Current K24 work shows that (a) IPS-DM are phenotypically and transcriptionally similar to their primary counterparts, (b) IPS-DM can be activated to functionally distinct M1 and M2 phenotypes, and (c) IPS-DM from Tangier disease patients reproduce disease specific macrophage phenotypes. Although recent genomic discoveries have identified multiple novel loci for CMD, the key challenge remains in defining the role of specific cell types, including macrophages, in causing disease. Alternative splicing (AS) plays a critical role in tissue and cell-specific functins but its role in macrophage phenotypes is also unknown. In preliminary studies, the Reilly group performed (a) CRISPR/Cas gene-editing in hiPSC of a LIPA, a novel loci for CAD, to study (in Aim 1) macrophage-specific functions of LIPA GWAS CAD risk alleles and (b) genome-wide RNA-seq analysis of splicing factors (SFs) in macrophages to explore (in Aim 2) a role for specific SFs (CELF1 and RBM43) and alternative splicing (AS) in macrophage- specific functions and human disease. Dr. Reilly will dedicate 25% effort to this K24 proposal (5% to augment his mentorship and POR skills; 5% to the research proposal; and 15% to mentoring). The K24 renewal will allow him to expand his mechanistic POR program while simultaneously dedicating experienced effort to train young clinical investigators.

Public Health Relevance

Dr. Reilly has a track record in unique mechanistic patient oriented research (POR) and mentorship at the University of Pennsylvania. His Cardiometabolic Research Program is dedicated to translational and genomic studies of human atherosclerosis and its risk factors. With current K24 support, he has had remarkable success in mentoring a new generation of POR researchers and in expanding his own POR PROGRAM. In this K24 renewal application, he proposes to (1) augment his scientific and mentoring skills and devote more time to mechanistic POR, (2) provide increased time and structure in mentoring new clinical investigators in the conduct of mechanistic POR, and (3) pursue new innovative POR in order to generate a unique training environment and framework for mentoring young clinical investigators to independent careers in POR.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL107643-10
Application #
9922979
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Wang, Wayne C
Project Start
2011-05-13
Project End
2021-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Zhang, Hanrui; Zhang, Nancy R; Li, Mingyao et al. (2018) First Giant Steps Toward a Cell Atlas of Atherosclerosis. Circ Res 122:1632-1634
Westerterp, Marit; Fotakis, Panagiotis; Ouimet, Mireille et al. (2018) Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis. Circulation 138:898-912
Ferguson, Jane F; Xue, Chenyi; Gao, Yuanfeng et al. (2018) Tissue-Specific Differential Expression of Novel Genes and Long Intergenic Noncoding RNAs in Humans With Extreme Response to Evoked Endotoxemia. Circ Genom Precis Med 11:e001907
Zhang, Hanrui; Shi, Jianting; Hachet, Melanie A et al. (2017) CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report. Arterioscler Thromb Vasc Biol 37:2156-2160
Zhang, Hanrui; Reilly, Muredach P (2017) LIPA Variants in Genome-Wide Association Studies of Coronary Artery Diseases: Loss-of-Function or Gain-of-Function? Arterioscler Thromb Vasc Biol 37:1015-1017
Saleheen, Danish; Zhao, Wei; Young, Robin et al. (2017) Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation 135:2336-2353
Zhang, Hanrui; Hinkle, Christine C; O'Neill, Sean M et al. (2017) Synergistic Modulation of Inflammatory but not Metabolic Effects of High-Fat Feeding by CCR2 and CX3CR1. Obesity (Silver Spring) 25:1410-1420
Zhang, Hanrui; Reilly, Muredach P (2017) Human Induced Pluripotent Stem Cell-Derived Macrophages for Unraveling Human Macrophage Biology. Arterioscler Thromb Vasc Biol 37:2000-2006
Qian, Jing; Nunez, Sara; Kim, Soohyun et al. (2017) A score test for genetic class-level association with nonlinear biomarker trajectories. Stat Med 36:3075-3091
Chen, Siying; Nunez, Sara; Reilly, Muredach P et al. (2017) Bayesian variable selection for post-analytic interrogation of susceptibility loci. Biometrics 73:603-614

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