Education

Postdoctoral Fellow
Harvard Medical School & Boston Children's Hospital, 2019
Whitman Center Fellow
Marine Biological Laboratory, Woods Hole, MA, 2016
Postdoctoral Fellow
Seoul National University, South Korea, 2012
Ph.D.
University of California, Irvine, 2010

Areas of Interest

Research Interests

 

Mechanoregulation of Cellular Adhesion and Migration

Cellular adhesion and migration require an intricate orchestration of membrane receptors and the cytoskeleton to transduce bidirectional force from extracellular substrates. When dysregulated, a myriad of pathologies can emerge from decreased immune extravasation (leukocyte adhesion deficiency), aberrant immune infiltration (rheumatoid arthritis, psoriasis, inflammatory bowel disease and atherosclerosis) and tumor metastasis via epithelial-mesenchymal transition. While the importance of the forces generated between cell-cell/ECM and the cytoskeleton are appreciated in cellular regulation, it is unknown how force sensing surface receptors and adhesion complexes dynamically respond to forces and transduce mechanical information. Integrins are one such family of cell surface mechanoreceptors.

Integrin signaling is complex due to their capacity to transmit signals bi-directionally from their extracellular ligand-binding domain, conveying information about substrate availability and stiffness, and from their cytoplasmic domains linking to signal transduction pathways. These intracellular signaling pathways transmit information from chemokine receptors to modulate the activation state of integrins and represent canonical inside-out signaling. Recent evidence supports another branch of inside-out signaling that involves a role for a mechanical component and the actin cytoskeleton. Integrin activation is dependent on their ability to transduce mechanical forces between the actin cytoskeleton and immobilized or cell surface-bound ligand. It is apparent that this force transduction acts as an allosteric effector resulting in integrin conformational change and associated changes in affinity, but the molecular mechanisms driving integrin activation and their regulation at the cellular level remain unclear and is essential to understanding how integrins function to mediate dynamic cellular adhesion and migration.

This cytoskeletal force model of integrin activation inherently links cell polarization and the actin cytoskeleton with integrin activation at the same location within the cell, preventing aberrant integrin-mediated adhesion by limiting active integrins only to where the cell can gain traction. To elucidate the mechanisms of actin’s mechanoregulation of integrin activation will require both functional studies and the development of new methods to measure actin cytoskeleton and integrin dynamics quantitatively. We will utilize super-resolution microscopy, computational image analysis, genome modification, and protein chemistry to understand the cytoskeleton’s linkage to integrins and directly measure integrin conformation on the cell surface, advancing our understanding of the regulation of cell adhesiveness and migration.

Publications

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Mise K, Long J, Galvan D, Ye Z, Fan G, Serysheva II, Moore TI, Wada J, Schumacker PT, Chang BH and Danesh FR. (2024) Improving Mitochondrial Respiration as a Strategy to Prevent Diabetic Kidney Disease Progression. Nature Communications. PMID: 37461606.

Zhu X*, Qi C*, Wang R*, Lee JH*, Shao J, Lanxin B. Xiong F, Nguyen PT, Li G, Krakowiak J, Koh S, Simon L, Han L, Moore TI, Li W. (2022). Acute Depletion of Human Core Nucleoporin Reveals Direct Roles in Transcription Control but Dispensability for 3D Genome Organization. Cell Reports. 41(5) 111576. PMID: 36323253.

Moore TI, Aaron J, Chew TL, and Springer TA, Measuring integrin conformational change on the cell surface with super-resolution microscopy. (2019) Cell Reports, 22 (7), 1903–1912. PMID: 29444440.

Moore TI*, Nordenfelt P*, Mehta SB*, Matthew JK, Swaminathan S, Nobuyasu K, Lambert TJ, Baker D, Waters JC, Oldenbourg R, Tani T, Mayor S, Waterman CM and Springer TA. (2017). Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. Nature Communications, 8(1), 673. PMID: 29229906.

Swaminathan V*, Matthew JK*, Mehta SB*, Nordenfelt P, Moore TI, Nobuyasu K, Baker D, Oldenbourg R, Tani T, Mayor S, Springer TA and Waterman CM. (2017). Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions. PNAS, 114(40) 40648-10653. PMID: 29073038.

Moore TI*, Chou CS*, Nie Q, and Yi TM. Alternative cell polarity behaviors arise from bifurcations in G-protein spatial dynamics. (2015). IET Systems Biology, 9(2) 52-63. PMID: 26029251.

Moore TI, Tanaka H, Kim KJ, Jeon NL, and Yi TM. (2013). Yeast G-proteins mediate directional sensing and polarization behaviors in response to changes in pheromone gradient direction. Molecular Biology of the Cell, 24(4) 521-534. PMID: 23255559.

Quinones GA, Moore TI, Nicholes K, Lee H, Sun L, Jeon NL, and Stephan JP. (2013) New wall-less plate technology enabling cell-based investigations. Blood, 21(7) 25-35. PMID: 23242998.

Moore TI*, Chou CS*, Chang S, Nie Q, and Yi TM. (2012) Signaling regulated endocytosis and exocytosis lead to mating pheromone concentration dependent morphologies in yeast. FEBS letters. 586(23). PMID: 23108052.

Moore TI, Chou CS, Jeon NL, Nie Q, and Yi TM. (2008) Robust spatial sensing of mating pheromone gradients by yeast cells. PLoS One, 3, e3865. PMID: 19052645.

Waksman R, McEwan PE, Moore TI, Kolodige FD, Hellinga DG, Seabron RC, Rychnovsky S, Vasek J, Scott RW, Virmani R. (2008) PhotoPoint photodynamic therapy promotes stabilization of atherosclerotic plaques and inhibits plaque progression. Journal of the American College of Cardiology, 52, 1024-1032. PMID: 18786486.

Deane JD, Kharas MG, Oak JS, Stiles LN, Luo J, Moore TI, Ji H, Rommel C, Cantley LC, Lane TE, and Fruman DA. (2007) T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling. Blood. 109, 2894-2902. PMID: 17164340.

Hess KL, Donahue AC, Ng KL, Moore TI, Oak J, and Fruman DA. (2004). Frontline: The p85alpha isoform of phosphoinositide 3-kinase is essential for a subset of B cell receptor-initiated signaling responses. European Journal of Immunology. 34, 2968-2976. PMID: 15384044.