Bruce Conklin, MD

Professor & Senior Investigator
Department of Medicine
Gladstone Institute of Cardiovascular Disease
+1 415 734-2000

Therapeutic Approaches to Genetic Disease

Genome Engineering
The late Richard Feynman once said, “What I cannot create, I do not understand.” Human genetics began as observational science, but newly developed genome-engineering tools now allow us to directly test the cellular consequences of discrete genetic changes. We have developed efficient methods to edit one residue at a time in living human induced pluripotent stem (iPS) cells, resulting in “isogenic” lines of iPS cells. These isogenic lines form models that are now yielding phenotypes that are helping to explain the molecular basis of several human diseases. We are constructing collections of these isogenic lines that carry a range of disease mutations, from the most severe (rare) to the moderate (common) forms of cardiomyopathy.

Precise Genome Editing for Human Therapy
The rapid development of genome engineering, such as with the CRISPR system, now allows us to contemplate using these tools for human therapy in selective tissues. Using genome editing to “fix” a disease gene has great promise, because it could permanently correct the disease. However, tremendous challenges remain to ensure that only a specific part of the genome is edited, without causing “off-target” DNA damage that could lead to cancer. We focused on developing therapeutic editing for diseases of the heart and retina, because each tissue has unique challenges and opportunities. The heart has many newly described gene mutations that result in lethal heart failure (cardiomyopathy). Genome engineering can be used to cure cardiomyopathy mutations and validate targets for drug therapy; however, current engineering methods will need to be greatly enhanced before it can be used in vivo in the heart. In contrast, the retina has the advantage of a limited number of cells that can be directly targeted for therapy. These properties could potentially cure blindness caused by many gene mutations that currently have no therapy. We are developing proof-of-concept therapeutic editing methods in the retina that can be expanded to other tissues, such as the heart.

Human Cardiac Disease Models
We use iPS cells to model the genetic causes of human cardiomyopathy. Surprisingly, little is known about many genes associated with heart failure, from cardiomyopathy to abnormal heart rhythm, that results in “sudden death.” The heart provides an ideal system to determine the molecular basis of gene associations in human genetics. Until recently, modeling human gene variants in human cardiac tissue has been impossible. Human iPS cells now allow us to produce cardiovascular tissues that are identical, except for a single gene that has been altered by genome engineering. Our efforts have already been used to uncover multiple disease phenotypes and targets for drug therapy.

CRISPR-Based Screens in Human Cardiac Disease Models
Recently, we developed CRISPR-inhibition (CRISPRi) cell lines for highthroughput gene inactivation of thousands of different genes. CRISPRi screens can be used to identify the molecular basis of development, so that we can construct more mature human tissues and improved disease models. These studies will also allow us to identify drug targets that could be used for treating cardiomyopathy and other major diseases. We are currently focused on finding new pathways to enhance cardiac regeneration. In the future, other versions of the CRISPR system could be used to activate genes and control the epigenetic state of the genome.

Future Directions
We are developing new genome engineering methods in human iPS cells to identify therapeutic targets in cardiac disease. We are using these same tools to develop strategies for therapeutic genome editing. The combination of human iPS cells and genome editing provide unprecedented opportunities to explore new areas of biology and discover new therapies for disease.

Selected Recent Publications
1. Mandegar MA, Huebsch N, Frolov E, SHin E, Weissman JS, Qi LS, So P-L, Conklin BR. (2016) CRISPR interference efficiently induces gene knockdown and models disease in iPSCs. Cell Stem Cell. 18 1-13, April 7, 2016
2. Huebsch N et al. (2015) Automated video-based analysis of contractility and calcium flux in human-induced pluripotent stem cell-derived cardiomyocytes cultured over different spatial scales. Tissue Eng. Part C Methods 21:467.
3. Ma Z et al. (2015) Self-organizing human cardiac microchambers mediated by geometric confinement. Nat. Commun. 6:7413.
4. Miyaoka Y et al. (2014) Isolation of single-base genome-edited human iPS cells without antibiotic selection. Nat. Methods 11:291.
5. Spencer CI et al. (2014) Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports 3:269.

Research Summary: 
Human Cardiovascular Genetics and Genome Engineering

Websites

Publications: 

Critical Roles of Translation Initiation and RNA Uridylation in Endogenous Retroviral Expression and Neural Differentiation in Pluripotent Stem Cells.

Cell reports

Takahashi K, Jeong D, Wang S, Narita M, Jin X, Iwasaki M, Perli SD, Conklin BR, Yamanaka S

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Nature communications

Wienert B, Nguyen DN, Guenther A, Feng SJ, Locke MN, Wyman SK, Shin J, Kazane KR, Gregory GL, Carter MAM, Wright F, Conklin BR, Marson A, Richardson CD, Corn JE

CRISPR off-target detection with DISCOVER-seq.

Nature protocols

Wienert B, Wyman SK, Yeh CD, Conklin BR, Corn JE

Maladaptive Contractility of 3D Human Cardiac Microtissues to Mechanical Nonuniformity.

Advanced healthcare materials

Wang C, Koo S, Park M, Vangelatos Z, Hoang P, Conklin BR, Grigoropoulos CP, Healy KE, Ma Z

Automated Design of Pluripotent Stem Cell Self-Organization.

Cell systems

Libby ARG, Briers D, Haghighi I, Joy DA, Conklin BR, Belta C, McDevitt TC

AlleleAnalyzer: a tool for personalized and allele-specific sgRNA design.

Genome biology

Keough KC, Lyalina S, Olvera MP, Whalen S, Conklin BR, Pollard KS

Abstract 934: Physical and Genetic Interaction Analyses in Human Pluripotent Stem Cell-Derived Cardiomyocytes to Study Protein Quality Control Disease in the Heart.

Circulation research

Juan A Perez-Bermejo, Luke M Judge, Kenneth Wu, Christina L Jensen, Robyn M Kaake, Danielle Swaney, Po-Lin So, Nevan J Krogan, Bruce R Conklin

Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells.

Stem cell reports

Yoshinaga D, Baba S, Makiyama T, Shibata H, Hirata T, Akagi K, Matsuda K, Kohjitani H, Wuriyanghai Y, Umeda K, Yamamoto Y, Conklin BR, Horie M, Takita J, Heike T

Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes.

Nature genetics

Song M, Yang X, Ren X, Maliskova L, Li B, Jones IR, Wang C, Jacob F, Wu K, Traglia M, Tam TW, Jamieson K, Lu SY, Ming GL, Li Y, Yao J, Weiss LA, Dixon JR, Judge LM, Conklin BR, Song H, Gan L, Shen Y

A NOVEL ROLE FOR THE FTD-CAUSING PROTEIN PROGRANULIN IN APOPTOSIS SIGNALING.

Alzheimer's & Dementia

Claire Clelland, J. Iker Etchegaray, Lay Kodama, Faten Sayed, Aradhana Sachdev, Yaqiao Li, David Le, Lihong Zhan, Yungui Zhou, Duc Duong, Nicholas T. Seyfried, Thomas G. Kukar, Li Xuan Tan, Aparna Lakkaraju, Bruce Conklin, Li Gan

Unbiased detection of CRISPR off-targets in vivo using DISCOVER-Seq.

Science (New York, N.Y.)

Wienert B, Wyman SK, Richardson CD, Yeh CD, Akcakaya P, Porritt MJ, Morlock M, Vu JT, Kazane KR, Watry HL, Judge LM, Conklin BR, Maresca M, Corn JE

MESP1 knock-down in human iPSC attenuates early vascular progenitor cell differentiation after completed primitive streak specification.

Developmental biology

Eskildsen TV, Ayoubi S, Thomassen M, Burton M, Mandegar MA, Conklin BR, Jensen CH, Andersen DC, Sheikh SP

Spatiotemporal mosaic self-patterning of pluripotent stem cells using CRISPR interference.

eLife

Libby AR, Joy DA, So PL, Mandegar MA, Muncie JM, Mendoza-Camacho FN, Weaver VM, Conklin BR, McDevitt TC

Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload.

Nature biomedical engineering

Ma Z, Huebsch N, Koo S, Mandegar MA, Siemons B, Boggess S, Conklin BR, Grigoropoulos CP, Healy KE

Quantitatively Characterizing Drug-Induced Arrhythmic Contractile Motions of Human Stem Cell-Derived Cardiomyocytes.

Biotechnology and bioengineering

Hoang P, Huebsch N, Bang SH, Siemons BA, Conklin BR, Healy KE, Ma Z, Jacquir S

Quantitatively Characterizing Drug-Induced Arrhythmic Contractile Motions of Human Stem Cell-Derived Cardiomyocytes.

Biotechnology and bioengineering

Plansky Hoang, Nathaniel Huebsch, Shin Hyuk Bang, Brian A. Siemons, Bruce R. Conklin, Kevin E. Healy, Zhen Ma, Sabir Jacquir

Detection and Quantification of HDR and NHEJ Induced by Genome Editing at Endogenous Gene Loci Using Droplet Digital PCR.

Methods in molecular biology (Clifton, N.J.)

Miyaoka Y, Mayerl SJ, Chan AH, Conklin BR

TMOD-09. HUMAN PLURIPOTENT STEM CELL-BASED MODELS OF NEUROBLASTOMA.

Neuro-oncology

Miller Huang, Tina Zheng, Jeffrey Guo, Colin Sperring, Matthew Miller, Lauren McHenry, Qiqi Zhen, Branden Moriarity, Marianne Bronner, Bruce Conklin, David Largaespada, John Maris, Katherine Matthay, William Weiss

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress.

JCI insight

Judge LM, Perez-Bermejo JA, Truong A, Ribeiro AJ, Yoo JC, Jensen CL, Mandegar MA, Huebsch N, Kaake RM, So PL, Srivastava D, Pruitt BL, Krogan NJ, Conklin BR

Multi-Imaging Method to Assay the Contractile Mechanical Output of Micropatterned Human iPSC-Derived Cardiac Myocytes.

Circulation research

Ribeiro AJS, Schwab O, Mandegar MA, Ang YS, Conklin BR, Srivastava D, Pruitt BL

CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells.

Science (New York, N.Y.)

Liu SJ, Horlbeck MA, Cho SW, Birk HS, Malatesta M, He D, Attenello FJ, Villalta JE, Cho MY, Chen Y, Mandegar MA, Olvera MP, Gilbert LA, Conklin BR, Chang HY, Weissman JS, Lim DA

Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system.

Nature medicine

Workman MJ, Mahe MM, Trisno S, Poling HM, Watson CL, Sundaram N, Chang CF, Schiesser J, Aubert P, Stanley EG, Elefanty AG, Miyaoka Y, Mandegar MA, Conklin BR, Neunlist M, Brugmann SA, Helmrath MA, Wells JM

GENT-49. SYSTEMATIC IDENTIFICATION OF ESSENTIAL LONG NON-CODING RNA GENES IN GLIOBLASTOMA.

Neuro-oncology

Siyuan Liu, Max Horlbeck, Seung Woo Cho, Harjus Birk, Martina Malatesta, Daniel He, Jacqueline Villalta, Min Cho, Yuwen Chen, Mohammad Mandegar, Michael Olvera, Bruce Conklin, Howard Chang, Jonathan Weissman, Daniel Lim

BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence.

Proceedings of the National Academy of Sciences of the United States of America

Hayashi Y, Hsiao EC, Sami S, Lancero M, Schlieve CR, Nguyen T, Yano K, Nagahashi A, Ikeya M, Matsumoto Y, Nishimura K, Fukuda A, Hisatake K, Tomoda K, Asaka I, Toguchida J, Conklin BR, Yamanaka S

Organs-on-a-chip – Microphysiological platforms as in vitro models of cardiac and adipose tissue.

Toxicology Letters

P. Loskill, A. Mathur, B.R. Conklin, A. Stahl, L.P. Lee, K.E. Healy

Detecting Single-Nucleotide Substitutions Induced by Genome Editing.

Cold Spring Harbor protocols

Miyaoka Y, Chan AH, Conklin BR

Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity.

Nature communications

Nguyen DP, Miyaoka Y, Gilbert LA, Mayerl SJ, Lee BH, Weissman JS, Conklin BR, Wells JA

Miniaturized iPS-Cell-Derived Cardiac Muscles for Physiologically Relevant Drug Response Analyses.

Scientific reports

Huebsch N, Loskill P, Deveshwar N, Spencer CI, Judge LM, Mandegar MA, Fox CB, Mohamed TM, Ma Z, Mathur A, Sheehan AM, Truong A, Saxton M, Yoo J, Srivastava D, Desai TA, So PL, Healy KE, Conklin BR

Systematic quantification of HDR and NHEJ reveals effects of locus, nuclease, and cell type on genome-editing.

Scientific reports

Miyaoka Y, Berman JR, Cooper SB, Mayerl SJ, Chan AH, Zhang B, Karlin-Neumann GA, Conklin BR

CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs.

Cell stem cell

Mandegar MA, Huebsch N, Frolov EB, Shin E, Truong A, Olvera MP, Chan AH, Miyaoka Y, Holmes K, Spencer CI, Judge LM, Gordon DE, Eskildsen TV, Villalta JE, Horlbeck MA, Gilbert LA, Krogan NJ, Sheikh SP, Weissman JS, Qi LS, So PL, Conklin BR

Generating trunk neural crest from human pluripotent stem cells.

Scientific reports

Huang M, Miller ML, McHenry LK, Zheng T, Zhen Q, Ilkhanizadeh S, Conklin BR, Bronner ME, Weiss WA

Efficient CRISPR/Cas9-Based Genome Engineering in Human Pluripotent Stem Cells.

Current protocols in human genetics

Kime C, Mandegar MA, Srivastava D, Yamanaka S, Conklin BR, Rand TA

Self-organizing human cardiac microchambers mediated by geometric confinement.

Nature communications

Ma Z, Wang J, Loskill P, Huebsch N, Koo S, Svedlund FL, Marks NC, Hua EW, Grigoropoulos CP, Conklin BR, Healy KE

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Acta neuropathologica

Nobuta H, Cilio MR, Danhaive O, Tsai HH, Tupal S, Chang SM, Murnen A, Kreitzer F, Bravo V, Czeisler C, Gokozan HN, Gygli P, Bush S, Weese-Mayer DE, Conklin B, Yee SP, Huang EJ, Gray PA, Rowitch D, Otero JJ

Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Wang L, Hsiao EC, Lieu S, Scott M, O'Carroll D, Urrutia A, Conklin BR, Colnot C, Nissenson RA

Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.

Proceedings of the National Academy of Sciences of the United States of America

Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJ

A non-invasive platform for functional characterization of stem-cell-derived cardiomyocytes with applications in cardiotoxicity testing.

Stem cell reports

Maddah M, Heidmann JD, Mandegar MA, Walker CD, Bolouki S, Conklin BR, Loewke KE

Human iPSC-based cardiac microphysiological system for drug screening applications.

Scientific reports

Mathur A, Loskill P, Shao K, Huebsch N, Hong S, Marcus SG, Marks N, Mandegar M, Conklin BR, Lee LP, Healy KE

Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive Gs-G protein signaling in osteoblasts.

Experimental cell research

Wattanachanya L, Wang L, Millard SM, Lu WD, O'Carroll D, Hsiao EC, Conklin BR, Nissenson RA

Gai/o-coupled receptor signaling restricts pancreatic ß-cell expansion.

Proceedings of the National Academy of Sciences of the United States of America

Berger M, Scheel DW, Macias H, Miyatsuka T, Kim H, Hoang P, Ku GM, Honig G, Liou A, Tang Y, Regard JB, Sharifnia P, Yu L, Wang J, Coughlin SR, Conklin BR, Deneris ES, Tecott LH, German MS

Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Nature neuroscience

Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L

Automated Video-Based Analysis of Contractility and Calcium Flux in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Cultured over Different Spatial Scales.

Tissue engineering. Part C, Methods

Huebsch N, Loskill P, Mandegar MA, Marks NC, Sheehan AS, Ma Z, Mathur A, Nguyen TN, Yoo JC, Judge LM, Spencer CI, Chukka AC, Russell CR, So PL, Conklin BR, Healy KE

Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia.

Stem cell reports

Spencer CI, Baba S, Nakamura K, Hua EA, Sears MA, Fu CC, Zhang J, Balijepalli S, Tomoda K, Hayashi Y, Lizarraga P, Wojciak J, Scheinman MM, Aalto-Setälä K, Makielski JC, January CT, Healy KE, Kamp TJ, Yamanaka S, Conklin BR

Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal.

Proceedings of the National Academy of Sciences of the United States of America

Park JS, Rhau B, Hermann A, McNally KA, Zhou C, Gong D, Weiner OD, Conklin BR, Onuffer J, Lim WA

Isolation of single-base genome-edited human iPS cells without antibiotic selection.

Nature methods

Miyaoka Y, Chan AH, Judge LM, Yoo J, Huang M, Nguyen TD, Lizarraga PP, So PL, Conklin BR

Human induced pluripotent stem cell-based microphysiological tissue models of myocardium and liver for drug development.

Stem cell research & therapy

Mathur A, Loskill P, Hong S, Lee J, Marcus SG, Dumont L, Conklin BR, Willenbring H, Lee LP, Healy KE

Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation.

Orphanet journal of rare diseases

Matsumoto Y, Hayashi Y, Schlieve CR, Ikeya M, Kim H, Nguyen TD, Sami S, Baba S, Barruet E, Nasu A, Asaka I, Otsuka T, Yamanaka S, Conklin BR, Toguchida J, Hsiao EC

Three-dimensional filamentous human diseased cardiac tissue model.

Biomaterials

Ma Z, Koo S, Finnegan MA, Loskill P, Huebsch N, Marks NC, Conklin BR, Grigoropoulos CP, Healy KE

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy.

Journal of molecular and cellular cardiology

Taglieri DM, Johnson KR, Burmeister BT, Monasky MM, Spindler MJ, DeSantiago J, Banach K, Conklin BR, Carnegie GK

A robust method to derive functional neural crest cells from human pluripotent stem cells.

American journal of stem cells

Kreitzer FR, Salomonis N, Sheehan A, Huang M, Park JS, Spindler MJ, Lizarraga P, Weiss WA, So PL, Conklin BR

AKAP13 Rho-GEF and PKD-binding domain deficient mice develop normally but have an abnormal response to ß-adrenergic-induced cardiac hypertrophy.

PloS one

Spindler MJ, Burmeister BT, Huang Y, Hsiao EC, Salomonis N, Scott MJ, Srivastava D, Carnegie GK, Conklin BR

Structure of a novel winged-helix like domain from human NFRKB protein.

PloS one

Kumar A, Möcklinghoff S, Yumoto F, Jaroszewski L, Farr CL, Grzechnik A, Nguyen P, Weichenberger CX, Chiu HJ, Klock HE, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Conklin BR, Fletterick RJ, Wilson IA

Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells.

Cell stem cell

Tomoda K, Takahashi K, Leung K, Okada A, Narita M, Yamada NA, Eilertson KE, Tsang P, Baba S, White MP, Sami S, Srivastava D, Conklin BR, Panning B, Yamanaka S

GO-Elite: a flexible solution for pathway and ontology over-representation.

Bioinformatics (Oxford, England)

Zambon AC, Gaj S, Ho I, Hanspers K, Vranizan K, Evelo CT, Conklin BR, Pico AR, Salomonis N

WikiPathways: building research communities on biological pathways.

Nucleic acids research

Kelder T, van Iersel MP, Hanspers K, Kutmon M, Conklin BR, Evelo CT, Pico AR

Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture.

Disease models & mechanisms

Lahti AL, Kujala VJ, Chapman H, Koivisto AP, Pekkanen-Mattila M, Kerkelä E, Hyttinen J, Kontula K, Swan H, Conklin BR, Yamanaka S, Silvennoinen O, Aalto-Setälä K

Mineral composition is altered by osteoblast expression of an engineered G(s)-coupled receptor.

Calcified tissue international

Kazakia GJ, Speer D, Shanbhag S, Majumdar S, Conklin BR, Nissenson RA, Hsiao EC

Blockade of receptor-activated G(i) signaling in osteoblasts in vivo leads to site-specific increases in cortical and cancellous bone formation.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Millard SM, Louie AM, Wattanachanya L, Wronski TJ, Conklin BR, Nissenson RA

Constitutive Gs activation using a single-construct tetracycline-inducible expression system in embryonic stem cells and mice.

Stem cell research & therapy

Hsiao EC, Nguyen TD, Ng JK, Scott MJ, Chang WC, Zahed H, Conklin BR

Stem cell pluripotency: alternative modes of transcription regulation.

Cell cycle (Georgetown, Tex.)

Salomonis N, Conklin BR

AltAnalyze and DomainGraph: analyzing and visualizing exon expression data.

Nucleic acids research

Emig D, Salomonis N, Baumbach J, Lengauer T, Conklin BR, Albrecht M

Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation.

Proceedings of the National Academy of Sciences of the United States of America

Salomonis N, Schlieve CR, Pereira L, Wahlquist C, Colas A, Zambon AC, Vranizan K, Spindler MJ, Pico AR, Cline MS, Clark TA, Williams A, Blume JE, Samal E, Mercola M, Merrill BJ, Conklin BR

Gs G protein-coupled receptor signaling in osteoblasts elicits age-dependent effects on bone formation.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Hsiao EC, Boudignon BM, Halloran BP, Nissenson RA, Conklin BR

Ligand-mediated activation of an engineered gs g protein-coupled receptor in osteoblasts increases trabecular bone formation.

Molecular endocrinology (Baltimore, Md.)

Hsiao EC, Millard SM, Louie A, Huang Y, Conklin BR, Nissenson RA

Cloning mice and men: prohibiting the use of iPS cells for human reproductive cloning.

Cell stem cell

Lo B, Parham L, Alvarez-Buylla A, Cedars M, Conklin B, Fisher S, Gates E, Giudice L, Halme DG, Hershon W, Kriegstein A, Kwok PY, Wagner R

The BridgeDb framework: standardized access to gene, protein and metabolite identifier mapping services.

BMC bioinformatics

van Iersel MP, Pico AR, Kelder T, Gao J, Ho I, Hanspers K, Conklin BR, Evelo CT

G(i)-coupled GPCR signaling controls the formation and organization of human pluripotent colonies.

PloS one

Nakamura K, Salomonis N, Tomoda K, Yamanaka S, Conklin BR

Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors.

PLoS computational biology

Salomonis N, Nelson B, Vranizan K, Pico AR, Hanspers K, Kuchinsky A, Ta L, Mercola M, Conklin BR

Mining biological pathways using WikiPathways web services.

PloS one

Kelder T, Pico AR, Hanspers K, van Iersel MP, Evelo C, Conklin BR

AKAP10 (I646V) functional polymorphism predicts heart rate and heart rate variability in apparently healthy, middle-aged European-Americans.

Psychophysiology

Neumann SA, Tingley WG, Conklin BR, Shrader CJ, Peet E, Muldoon MF, Jennings JR, Ferrell RE, Manuck SB

Endogenous Gi signaling in osteoblasts participates in sexually dimorphic regulation of cancellous bone structure.

Bone

S. Millard, A. Louie, C. Manalac, W. Lu, N. Cotte, T.J. Wronski, B. Conklin, R.A. Nissenson

Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes.

PloS one

Kita-Matsuo H, Barcova M, Prigozhina N, Salomonis N, Wei K, Jacot JG, Nelson B, Spiering S, Haverslag R, Kim C, Talantova M, Bajpai R, Calzolari D, Terskikh A, McCulloch AD, Price JH, Conklin BR, Chen HS, Mercola M

SNPLogic: an interactive single nucleotide polymorphism selection, annotation, and prioritization system.

Nucleic acids research

Pico AR, Smirnov IV, Chang JS, Yeh RF, Wiemels JL, Wiencke JK, Tihan T, Conklin BR, Wrensch M

Presenting and exploring biological pathways with PathVisio.

BMC bioinformatics

van Iersel MP, Kelder T, Pico AR, Hanspers K, Coort S, Conklin BR, Evelo C

Engineering GPCR signaling pathways with RASSLs.

Nature methods

Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S, Forsayeth JR, Guettier JM, Chang WC, Pei Y, McCarthy KD, Nissenson RA, Wess J, Bockaert J, Roth BL

WikiPathways: pathway editing for the people.

PLoS biology

Pico AR, Kelder T, van Iersel MP, Hanspers K, Conklin BR, Evelo C

Marking embryonic stem cells with a 2A self-cleaving peptide: a NKX2-5 emerald GFP BAC reporter.

PloS one

Hsiao EC, Yoshinaga Y, Nguyen TD, Musone SL, Kim JE, Swinton P, Espineda I, Manalac C, deJong PJ, Conklin BR

An Introduction to Pathway Analysis with GenMAPP.

NCI Nature Pathway Interaction Database

Kristina Hanspers, Alexander R. Pico, Nathan Salomonis, Alexander C. Zambon, Karen Vranizan, Steven C. Lawlor, Kam D. Dahlquist, Scott W. Doniger, Bruce R. Conklin

MicroRNA regulation of cell lineages in mouse and human embryonic stem cells.

Cell stem cell

Ivey KN, Muth A, Arnold J, King FW, Yeh RF, Fish JE, Hsiao EC, Schwartz RJ, Conklin BR, Bernstein HS, Srivastava D

Osteoblast expression of an engineered Gs-coupled receptor dramatically increases bone mass.

Proceedings of the National Academy of Sciences of the United States of America

Hsiao EC, Boudignon BM, Chang WC, Bencsik M, Peng J, Nguyen TD, Manalac C, Halloran BP, Conklin BR, Nissenson RA

Modifying ligand-induced and constitutive signaling of the human 5-HT4 receptor.

PloS one

Chang WC, Ng JK, Nguyen T, Pellissier L, Claeysen S, Hsiao EC, Conklin BR

Conditional expression of a Gi-coupled receptor in osteoblasts results in trabecular osteopenia.

Endocrinology

Peng J, Bencsik M, Louie A, Lu W, Millard S, Nguyen P, Burghardt A, Majumdar S, Wronski TJ, Halloran B, Conklin BR, Nissenson RA

Modeling insertional mutagenesis using gene length and expression in murine embryonic stem cells.

PloS one

Nord AS, Vranizan K, Tingley W, Zambon AC, Hanspers K, Fong LG, Hu Y, Bacchetti P, Ferrin TE, Babbitt PC, Doniger SW, Skarnes WC, Young SG, Conklin BR

GenMAPP 2: new features and resources for pathway analysis.

BMC bioinformatics

Salomonis N, Hanspers K, Zambon AC, Vranizan K, Lawlor SC, Dahlquist KD, Doniger SW, Stuart J, Conklin BR, Pico AR

Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors.

Proceedings of the National Academy of Sciences of the United States of America

Kwon C, Arnold J, Hsiao EC, Taketo MM, Conklin BR, Srivastava D

Interfacing silicon nanowires with mammalian cells.

Journal of the American Chemical Society

Kim W, Ng JK, Kunitake ME, Conklin BR, Yang P

Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation.

Proceedings of the National Academy of Sciences of the United States of America

Tingley WG, Pawlikowska L, Zaroff JG, Kim T, Nguyen T, Young SG, Vranizan K, Kwok PY, Whooley MA, Conklin BR

New tools to build synthetic hormonal pathways.

Proceedings of the National Academy of Sciences of the United States of America

Conklin BR

Development of hydrocephalus in mice expressing the G(i)-coupled GPCR Ro1 RASSL receptor in astrocytes.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Sweger EJ, Casper KB, Scearce-Levie K, Conklin BR, McCarthy KD

Integration of biological networks and gene expression data using Cytoscape.

Nature protocols

Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, Christmas R, Avila-Campilo I, Creech M, Gross B, Hanspers K, Isserlin R, Kelley R, Killcoyne S, Lotia S, Maere S, Morris J, Ono K, Pavlovic V, Pico AR, Vailaya A, Wang PL, Adler A, Conklin BR, Hood L, Kuiper M, Sander C, Schmulevich I, Schwikowski B, Warner GJ, Ideker T, Bader GD

mGluR2 acts through inhibitory Galpha subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses.

Proceedings of the National Academy of Sciences of the United States of America

Nicholls RE, Zhang XL, Bailey CP, Conklin BR, Kandel ER, Stanton PK

The International Gene Trap Consortium Website: a portal to all publicly available gene trap cell lines in mouse.

Nucleic acids research

Nord AS, Chang PJ, Conklin BR, Cox AV, Harper CA, Hicks GG, Huang CC, Johns SJ, Kawamoto M, Liu S, Meng EC, Morris JH, Rossant J, Ruiz P, Skarnes WC, Soriano P, Stanford WL, Stryke D, von Melchner H, Wurst W, Yamamura K, Young SG, Babbitt PC, Ferrin TE

Sustained preconditioning induced by cardiac transgenesis with the tetracycline transactivator.

American journal of physiology. Heart and circulatory physiology

Turnbull L, Zhou HZ, Swigart PM, Turcato S, Karliner JS, Conklin BR, Simpson PC, Baker AJ

Gene expression patterns define key transcriptional events in cell-cycle regulation by cAMP and protein kinase A.

Proceedings of the National Academy of Sciences of the United States of America

Zambon AC, Zhang L, Minovitsky S, Kanter JR, Prabhakar S, Salomonis N, Vranizan K, Dubchak I, Conklin BR, Insel PA

Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression.

Physiological genomics

McCloskey DT, Turnbull L, Swigart PM, Zambon AC, Turcato S, Joho S, Grossman W, Conklin BR, Simpson PC, Baker AJ

Identifying genetic networks underlying myometrial transition to labor.

Genome biology

Salomonis N, Cotte N, Zambon AC, Pollard KS, Vranizan K, Doniger SW, Dolganov G, Conklin BR

Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans.

The Journal of clinical investigation

Srinivasan S, Lubrano-Berthelier C, Govaerts C, Picard F, Santiago P, Conklin BR, Vaisse C

A public gene trap resource for mouse functional genomics.

Nature genetics

Skarnes WC, von Melchner H, Wurst W, Hicks G, Nord AS, Cox T, Young SG, Ruiz P, Soriano P, Tessier-Lavigne M, Conklin BR, Stanford WL, Rossant J

Time- and exercise-dependent gene regulation in human skeletal muscle.

Genome biology

Zambon AC, McDearmon EL, Salomonis N, Vranizan KM, Johansen KL, Adey D, Takahashi JS, Schambelan M, Conklin BR

Engineering the melanocortin-4 receptor to control G(s) signaling in vivo.

Annals of the New York Academy of Sciences

Srinivasan S, Vaisse C, Conklin BR

MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data.

Genome biology

Doniger SW, Salomonis N, Dahlquist KD, Vranizan K, Lawlor SC, Conklin BR

Regression approaches for microarray data analysis.

Journal of computational biology : a journal of computational molecular cell biology

Segal MR, Dahlquist KD, Conklin BR

GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways.

Nature genetics

Dahlquist KD, Salomonis N, Vranizan K, Lawlor SC, Conklin BR

Tools for dissecting signaling pathways in vivo: receptors activated solely by synthetic ligands.

Methods in enzymology

Scearce-Levie K, Coward P, Redfern CH, Conklin BR

Engineering receptors activated solely by synthetic ligands (RASSLs).

Trends in pharmacological sciences

Scearce-Levie K, Coward P, Redfern CH, Conklin BR

Abnormal contraction caused by expression of G(i)-coupled receptor in transgenic model of dilated cardiomyopathy.

American journal of physiology. Heart and circulatory physiology

Baker AJ, Redfern CH, Harwood MD, Simpson PC, Conklin BR

Tetracycline-inducible system for photoreceptor-specific gene expression.

Investigative ophthalmology & visual science

Chang MA, Horner JW, Conklin BR, DePinho RA, Bok D, Zack DJ

Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy.

Proceedings of the National Academy of Sciences of the United States of America

Redfern CH, Degtyarev MY, Kwa AT, Salomonis N, Cotte N, Nanevicz T, Fidelman N, Desai K, Vranizan K, Lee EK, Coward P, Shah N, Warrington JA, Fishman GI, Bernstein D, Baker AJ, Conklin BR

A critical period of vulnerability to hyperactive Gq signaling revealed by inducible and heart-specific expression of Gq* in transgenic mice.

Journal of Cardiac Failure

Nathalie Cotte, Charles H. Redfern, Peter Mikus, Nathan Salomonis, Michael Y. Degtyarev, Peter S. Coward, Andrew Kwa, Tetsuo Shioi, Nila Shah, Tim McKinsey, Eric Olson, Seigo Izumo, Janet Warrington, Anthony J. Baker, Bruce R. Conklin

Genomic analysis of an inducible and reversible model of dilated cardiomyopathy.

Journal of Cardiac Failure

Charles H. Redfern, Michael Y. Degtyarev, Kavin Desai, Andrew Kwa, Glenn I. Fishman, Daniel Bernstein, Anthony J. Baker, Bruce R. Conklin

Chimeric G proteins allow a high-throughput signaling assay of Gi-coupled receptors.

Analytical biochemistry

Coward P, Chan SD, Wada HG, Humphries GM, Conklin BR

Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice.

Nature biotechnology

Redfern CH, Coward P, Degtyarev MY, Lee EK, Kwa AT, Hennighausen L, Bujard H, Fishman GI, Conklin BR

Controlling signaling with a specifically designed Gi-coupled receptor.

Proceedings of the National Academy of Sciences of the United States of America

Coward P, Wada HG, Falk MS, Chan SD, Meng F, Akil H, Conklin BR

The N-terminal extension of Galphaq is critical for constraining the selectivity of receptor coupling.

The Journal of biological chemistry

Kostenis E, Degtyarev MY, Conklin BR, Wess J

Interactions of muscarinic receptors with the heterotrimeric G proteins Gq and G12: transduction of proliferative signals.

Journal of neurochemistry

Burstein ES, Bräuner-Osborne H, Spalding TA, Conklin BR, Brann MR

Carboxyl-terminal mutations of Gq alpha and Gs alpha that alter the fidelity of receptor activation.

Molecular pharmacology

Conklin BR, Herzmark P, Ishida S, Voyno-Yasenetskaya TA, Sun Y, Farfel Z, Bourne HR

Identification of a receptor/G-protein contact site critical for signaling specificity and G-protein activation.

Proceedings of the National Academy of Sciences of the United States of America

Liu J, Conklin BR, Blin N, Yun J, Wess J

G alpha 13 stimulates Na-H exchange.

The Journal of biological chemistry

Voyno-Yasenetskaya T, Conklin BR, Gilbert RL, Hooley R, Bourne HR, Barber DL

Mouse coat colour reconsidered.

Nature

Conklin BR, Bourne HR

Type II adenylylcyclase integrates coincident signals from Gs, Gi, and Gq.

The Journal of biological chemistry

Lustig KD, Conklin BR, Herzmark P, Taussig R, Bourne HR

A recombinant calcitonin receptor independently stimulates 3',5'-cyclic adenosine monophosphate and Ca2+/inositol phosphate signaling pathways.

Molecular endocrinology (Baltimore, Md.)

Chabre O, Conklin BR, Lin HY, Lodish HF, Wilson E, Ives HE, Catanzariti L, Hemmings BA, Bourne HR

Hormonal stimulation of adenylyl cyclase through Gi-protein beta gamma subunits.

Nature

Federman AD, Conklin BR, Schrader KA, Reed RR, Bourne HR

Gz-mediated hormonal inhibition of cyclic AMP accumulation.

Science (New York, N.Y.)

Wong YH, Conklin BR, Bourne HR

Recombinant Gq alpha. Mutational activation and coupling to receptors and phospholipase C.

The Journal of biological chemistry

Conklin BR, Chabre O, Wong YH, Federman AD, Bourne HR

Detection of coincident signals by G proteins and adenylyl cyclase.

Cold Spring Harbor symposia on quantitative biology

Bourne HR, Lustig KD, Wong YH, Conklin BR

Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned genes for muscarinic receptor subtypes stably expressed in A9 L cells.

Proceedings of the National Academy of Sciences of the United States of America

Conklin BR, Brann MR, Buckley NJ, Ma AL, Bonner TI, Axelrod J

Distinct bradykinin receptors mediate stimulation of prostaglandin synthesis by endothelial cells and fibroblasts.

The Journal of pharmacology and experimental therapeutics

Conklin BR, Burch RM, Steranka LR, Axelrod J