Brian L. Lin, PhD

Assistant Professor

Locations

Cell Biology, Neurobiology & Anatomy

Contact Information

Education

Postdoctoral Fellow, Johns Hopkins 91大神 Institutions, 2023
PhD, Loyola University, 2016
BS, Miami University, 2008

Biography

Brian Lin started his research career in Marine Biology during his undergraduate studies at Miami University, where Brian also studied skeletal muscle in birds and amphibians. After graduating in 2008, Brian worked as a behavioral neuroscience technician at Cincinnati Children's Hospital and Northwestern University. From 2011 - 2016, Brian studied Cell and Molecular Physiology at Loyola University Chicago focusing on the role of skeletal muscle myofilament proteins in the lab of Sakthivel Sadayappan. From 2016-2023, Brian studied the role of TRP channels in heart and kidney disease in the lab of David Kass in the Division of Cardiology at Johns Hopkins. From that work, Brian focused on the role of TRPC6 in the context of Duchenne muscular dystrophy for which he was awarded a K99/R00 award. Brian started his independent lab in the Department of Cell Biology, Neurobiology, and Anatomy at the 91大神 College of Wisconsin, where he continues to study novel therapeutics targeting TRP channels to treat dystrophic cardiomyopathy.

Research Interests

The overarching goal of my research is to investigate mechanosensitive ion channel signaling in cardiac and skeletal muscle diseases. Full description My current research focuses on testing novel therapies in mouse and human models of Duchenne muscular dystrophy (DMD). DMD is caused by a loss of dystrophin, resulting in progressive muscle weakness and immobility, severe spinal deformities, pathological fibrosis, heart failure, and early mortality. The muscle weakness and loss of the ability to walk are the symptoms most commonly associated with DMD. However, most DMD patients eventually succumb to cardiac failure, as the heart is also a muscle. In muscle cells, loss of dystrophin destabilizes the sarcolemma membrane which hyperactivates mechanosensitive cation (notably Ca2+) channels and downstream fibrotic signaling, cell damage and death, and cardiac arrhythmia. We identified TRPC6 (transient receptor potential – canonical 6) as one such mechanosensitive ion channel hyperactivated in DMD. TRPC6-dependent excess Ca2+ influx resulted in hypercontraction and arrhythmia in beating DMD cardiomyocytes subjected to acute mechanical load. Breeding severe mdx/utrn-/- DMD mice into the TRPC6-null background improves cardiac and skeletal muscle function, and extended the lifespan of by 2-3 fold. Using new and specific TRPC6 inhibitors in mouse models and in vitro human stem cell models of DMD show normalization of Ca2+ transients and improvement in cardiac contraction. We show TRPC6 inhibition works to treat DMD. Our goal is to determine how. Mechanosensative Ion Channels and Inflammation One striking discovery was the localization of myocardial damage in DMD hearts that was attenuated with TRPC6 inhibition. Using traditional histology as a guide, I applied spatial transcriptomics and proteomics to these hearts to investigate potential causes. Gene set enrichment analysis identified signaling associated with inflammatory cytokines. Circulating cytokines in DMD mice show that systemic inflammatory signaling is indeed mediated by TRPC6 in DMD. TRPC6 inhibition reduces classic pro-inflammatory cytokines, such as TNFα, and promoted anti-inflammatory cytokines such as IL-10. Therefore, we seek to determine the precise source and localization of these cytokines and their impact on myocyte function. The Role of Copper in Myocytes Furthermore, signaling involving copper (Cu+) or use Cu+ as a cofactor was identified enriched within areas of myocardial damage. Preliminary analysis using laser-ablated mass spec shows elevated Cu+ in the muscles of our DMD mice, and is consistent with human DMD biopsy data that shows only two elevated ions – Cu+ and Ca2+. While Ca2+ has been well-studied in DMD, the role of Cu+ in DMD hearts remains unknown. Therefore, we seek to combine traditional histology with spatial -omics and mass spectrometry to elucidate the role of Cu+ in DMD and determine the therapeutic efficacy of TRPC6 inhibition to attenuate excess Cu+ in DMD. Mechanical Stress Mechanisms in the Heart Finally, we demonstrate a link between Ca2+/calmodulin-dependent protein kinase II (CaMKII) and TRPC6-mediated mechanosensitive signaling. CaMKII and TRPC6 appear to require one another to regulate mechanical stress responses in the heart, and the dysregulation of one is thought to exacerbate the pathological signaling of the other. Therefore, using both mouse and human induced pluripotent stem cell-derived cardiomyocytes, we seek to determine the impact of TRPC6 inhibition on mitigating the vicious feed-forward signaling between CaMKII and TRPC6.

(Meddeb M, Koleini N, Jun S, Keykhaei M, Farshidfar F, Zhao L, Kwon S, Lin B, Keceli G, Paolocci N, Hahn V, Sharma K, Pearce EL, Kass DA.) bioRxiv. 2024 Jun 10 PMID: 38915649 PMCID: PMC11195057 06/25/2024
(Hart CC, Lee YI, Xie J, Gao G, Lin BL, Hammers DW, Sweeney HL.) JCI Insight. 2024 May 07;9(11) PMID: 38713520 PMCID: PMC11382885 05/07/2024
(Diny NL, Wood MK, Won T, Talor MV, Lukban C, Bedja D, Wang N, Kalinoski H, Daoud A, Talbot CC Jr, Leei Lin B, 膶iháková D.) iScience. 2023 Oct 20;26(10):107990 PMID: 37829205 PMCID: PMC10565781 10/13/2023
(Fitch ML, Kabir R, Ebenebe OV, Taube N, Garbus H, Sinha P, Wang N, Mishra S, Lin BL, Muller GK, Kohr MJ.) Life Sci. 2023 Jul 01;324:121712 PMID: 37100378 PMCID: PMC10246466 04/27/2023
(Reyes Gaido OE, Pavlaki N, Granger JM, Mesubi OO, Liu B, Lin BL, Long A, Walker D, Mayourian J, Schole KL, Terrillion CE, Nkashama LJ, Hulsurkar MM, Dorn LE, Ferrero KM, Huganir RL, Müller FU, Wehrens XHT, Liu JO, Luczak ED, Bezzerides VJ, Anderson ME.) Sci Transl Med. 2023 Jun 21;15(701):eabq7839 PMID: 37343080 PMCID: PMC11022683 06/21/2023
(Kannan S, Miyamoto M, Zhu R, Lynott M, Guo J, Chen EZ, Colas AR, Lin BL, Kwon C.) Cell Rep. 2023 Apr 25;42(4):112330 PMID: 37014753 PMCID: PMC10545814 04/05/2023
(Lin BL, Shin JY, Jeffreys WP, Wang N, Lukban CA, Moorer MC, Velarde E, Hanselman OA, Kwon S, Kannan S, Riddle RC, Ward CW, Pullen SS, Filareto A, Kass DA.) JCI Insight. 2022 Oct 10;7(19) PMID: 36099033 PMCID: PMC9675567 09/14/2022
(Boyer JG, Huo J, Han S, Havens JR, Prasad V, Lin BL, Kass DA, Song T, Sadayappan S, Khairallah RJ, Ward CW, Molkentin JD.) Nat Commun. 2022 May 26;13(1):2940 PMID: 35618700 PMCID: PMC9135721 05/27/2022
(Tampakakis E, Gangrade H, Glavaris S, Htet M, Murphy S, Lin BL, Liu T, Saberi A, Miyamoto M, Kowalski W, Mukouyama YS, Lee G, Minichiello L, Kwon C.) Sci Adv. 2021 Dec 03;7(49):eabh4181 PMID: 34851661 PMCID: PMC8635446 12/02/2021
(Kannan S, Farid M, Lin BL, Miyamoto M, Kwon C.) PLoS Comput Biol. 2021 Sep;17(9):e1009305 PMID: 34534204 PMCID: PMC8448341 09/18/2021
(Verma RX, Kannan S, Lin BL, Fomchenko KM, Nieuwenhuis TO, Patil AH, Lukban C, Yang X, Fox-Talbot K, McCall MN, Kwon C, Kass DA, Rosenberg AZ, Halushka MK.) Skelet Muscle. 2021 May 17;11(1):13 PMID: 34001262 PMCID: PMC8127317 05/19/2021
(Chan XY, Volkova E, Eoh J, Black R, Fang L, Gorashi R, Song J, Wang J, Elliott MB, Barreto-Ortiz SF, Chen J, Lin BL, Santhanam L, Cheng L, Lee FS, Prchal JT, Gerecht S.) iScience. 2021 Apr 23;24(4):102246 PMID: 33796838 PMCID: PMC7995528 04/03/2021

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