Douglas Gould, PhD

Professor

Ophthalmology

Research Interests

Vascular and systemic diseases of the extracellular matrix

[email protected]

+1 415 476-3592

Websites

https://ophthalmology.ucsf.edu/gouldlab/

Faculty Type

Core CVRI Faculty

The Gould Lab studies the biological functions of basement membranes—specialized extracellular matrix structures that are essential for the development, function, and maintenance of every organ. Our research focuses on type IV collagen, particularly the COL4A1 and COL4A2 genes, whose mutations cause a multisystem disorder affecting the brain, eye, kidney, skeletal muscle, and other tissues. By combining human genetics, mouse models, cell biology, and physiology, we investigate how defects in a ubiquitous extracellular matrix protein produce tissue-specific disease and identify the molecular mechanisms that underlie cerebrovascular disease, glaucoma, kidney disease, myopathy, and other manifestations.

A central goal of the lab is to translate fundamental biological discoveries into new therapeutic strategies. We develop and use experimental models to define disease mechanisms, understand why patients with similar mutations can have very different clinical outcomes, and identify genetic and environmental factors that modify disease severity. These studies have helped establish the clinical and biological framework for what is now known as Gould syndrome and continue to guide efforts toward mechanism-based therapies and precision medicine. More broadly, our work seeks to advance understanding of how basement membranes regulate development, vascular integrity, tissue homeostasis, and aging, with implications that extend well beyond rare genetic disorders.

Publications

Collagen IV in Gould syndrome and Alport syndrome.

Nature reviews. Nephrology

Massoudi D, Miner JH, Gould DB

COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management.

Genetics in medicine : official journal of the American College of Medical Genetics

Tambala D, Vassar R, Snow J, Balestrini S, Bersano A, Guey S, Bonaventura E, Signorini S, Sartori S, Bertini E, Tonduti D, Parazzini C, Macchiaiolo M, Pelizza MF, Pichiecchio A, Massella L, Coste T, Orcesi S, Politano D, Bacci G, Marziali E, Dollfus H, Mandelli A, Chinali M, Plaisier E, Simioni P, Colombatti R, Guerrini R, Tournier-Lasserve E, Gould DB, Musolino PL

A multifunction murine Col4a1 allele reveals potential gene therapy parameters for Gould syndrome.

The Journal of Cell Biology

Mao M, Ishikawa Y, Labelle-Dumais C, Wang X, Kuo YM, Gaffney UB, Smith ME, Abdala CN, Lebedev MD, Paradee WJ, Gould DB

Skeletal pathology in mouse models of Gould syndrome is partially alleviated by genetically reducing TGFβ signaling.

Matrix biology : journal of the International Society for Matrix Biology

Labelle-Dumais C, Mazur C, Kaya S, Obata Y, Lee B, Acevedo C, Alliston T, Gould DB

Evaluating neural crest cell migration in a Col4a1 mutant mouse model of ocular anterior segment dysgenesis.

Cells & development

Cozzitorto C, Peltz Z, Flores LM, Della Santina L, Mao M, Gould DB

TGFß Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage.

Investigative ophthalmology & visual science

Mao M, Kuo YM, Yu AK, Labelle-Dumais C, Ou Y, Gould DB

Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.

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

Yin M, Smith JA, Chou M, Chan J, Jittayasothorn Y, Gould DB, Caspi RR, Anderson MS, DeFranco AL

Impaired intracellular Ca2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice.

Science signaling

Yamasaki E, Thakore P, Ali S, Sanchez Solano A, Wang X, Gao X, Labelle-Dumais C, Chaumeil MM, Gould DB, Earley S

Local Net Charge State of Collagen Triple Helix Is a Determinant of FKBP22 Binding to Collagen III.

International journal of molecular sciences

Ishikawa Y, Bonna A, Gould DB, Farndale RW

PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease.

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

Thakore P, Yamasaki E, Ali S, Sanchez Solano A, Labelle-Dumais C, Gao X, Chaumeil MM, Gould DB, Earley S

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

Intensive care medicine

Kjær MN, Meyhoff TS, Sivapalan P, Granholm A, Hjortrup PB, Madsen MB, Møller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Ostermann M, Gould D, Cecconi M, Malbrain MLNG, Ahlstedt C, Kiel LB, Bestle MH, Nebrich L, Hildebrandt T, Russell L, Vang M, Rasmussen ML, Sølling C, Brøchner AC, Krag M, Pfortmueller C, Kriz M, Siegemund M, Albano G, Aagaard SR, Bundgaard H, Crone V, Wichmann S, Johnstad B, Martin YK, Seidel P, Mårtensson J, Hollenberg J, Wistrand M, Donati A, Barbara E, Karvunidis T, Hollinger A, Carsetti A, Lumlertgul N, Joelsson-Alm E, Lambiris N, Aslam TN, Friberg FF, Vesterlund GK, Mortensen CB, Vestergaard SR, Caspersen SF, Jensen DB, Borup M, Rasmussen BS, Perner A

Deletion of the Unfolded Protein Response Transducer IRE1α Is Detrimental to Aging Photoreceptors and to ER Stress-Mediated Retinal Degeneration.

Investigative ophthalmology & visual science

Massoudi D, Gorman S, Kuo YM, Iwawaki T, Oakes SA, Papa FR, Gould DB

PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease.

bioRxiv : the preprint server for biology

Thakore P, Yamasaki E, Ali S, Solano AS, Labelle-Dumais C, Gao X, Chaumeil MM, Gould DB, Earley S

Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome.

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

Yamasaki E, Ali S, Sanchez Solano A, Thakore P, Smith M, Wang X, Labelle-Dumais C, Gould DB, Earley S

Elevated TGFβ signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome.

Matrix biology : journal of the International Society for Matrix Biology

Branyan K, Labelle-Dumais C, Wang X, Hayashi G, Lee B, Peltz Z, Gorman S, Li BQ, Mao M, Gould DB

Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).

The Journal of biological chemistry

Ishikawa Y, Taga Y, Coste T, Tufa SF, Keene DR, Mizuno K, Tournier-Lasserve E, Gould DB

Implementation of ReSPECT in acute hospitals: A retrospective observational study.

Resuscitation

Hawkes CA, Griffin J, Eli K, Griffiths F, Slowther AM, Fritz Z, Underwood M, Baldock C, Gould D, Lilford R, Jacques C, Warwick J, Perkins GD

Elevated TGFβ signaling contributes to ocular anterior segment dysgenesis in Col4a1 mutant mice.

Matrix biology : journal of the International Society for Matrix Biology

Mao M, Labelle-Dumais C, Tufa SF, Keene DR, Gould DB

Autoantigen specific T-cell receptor induces organ-specific autoimmunity by escaping T cell negative selection.

The Journal of Immunology

Mianmian Yin, Jennifer A Smith, Marissa Chou, Jackie Chan, Yongmei Hu, Clifford A Lowell, Douglas B Gould, Mark S Anderson, Anthony L DeFranco

Development of uveitis in a mouse model of spontaneous autoimmunity correlates with frequency of autoantigen-specific regulatory T cells.

The Journal of Immunology

Mianmian Yin, Kamir J Hiam, Irina Proekt, Jackie Chan, Yongmei Hu, Clifford A Lowell, Douglas B Gould, Matthew Spitzer, Mark S Anderson, Anthony L DeFranco

COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage.

Prenatal diagnosis

Coste T, Vincent-Delorme C, Stichelbout M, Devisme L, Gelot A, Deryabin I, Pelluard F, Aloui C, Leutenegger AL, Jouannic JM, Héron D, Gould DB, Tournier-Lasserve E

Epilepsy and related challenges in children with COL4A1 and COL4A2 mutations: A Gould syndrome patient registry.

Epilepsy & behavior : E&B

Boyce D, McGee S, Shank L, Pathak S, Gould D

Expanding the horizon of research into the pathogenesis of the white matter diseases: Proceedings of the 2021 Annual Workshop of the Albert Research Institute for White Matter and Cognition.

GeroScience

Whitehead SN, Bruno A, Burns JM, Carmichael ST, Csiszar A, Edwards JD, Elahi FM, Faraco G, Gould DB, Gustafson DR, Hachinski V, Rosenberg G, Sorond FA, Shih AY, Tse KH, Ungvari Z, Wilcock DM, Zuloaga KL, Barone FC

Correlation of autoantigen-specific Treg frequency with development of spontaneous organ-specific autoimmunity in a mouse model of uveitis.

The Journal of Immunology

Mianmian Yin, Kamir Hiam, Irina Proekt, Jackie Chan, Yongmei Hu, Clifford A Lowell, Douglas B Gould, Mark S Anderson, Anthony L DeFranco

T-cell receptor repertoire of mice with organ-specific autoimmunity resulting from a partial defect in T cell negative selection and dendritic cell enhancement.

The Journal of Immunology

Mianmian Yin, Jennifer A Smith, Marissa Chou, Jackie Chan, Yongmei Hu, Clifford A Lowell, Douglas B Gould, Mark S Anderson, Anthony L DeFranco

Identification of fibronectin 1 as a candidate genetic modifier in a Col4a1 mutant mouse model of Gould syndrome.

Disease models & mechanisms

Mao M, Popli T, Jeanne M, Hoff K, Sen S, Gould DB

Type I and type V procollagen triple helix uses different subsets of the molecular ensemble for lysine posttranslational modifications in the rER.

The Journal of biological chemistry

Ishikawa Y, Taga Y, Zientek K, Mizuno N, Salo AM, Semenova O, Tufa SF, Keene DR, Holden P, Mizuno K, Gould DB, Myllyharju J, Bächinger HP

Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta.

PLoS genetics

Syx D, Ishikawa Y, Gebauer J, Boudko SP, Guillemyn B, Van Damme T, D'hondt S, Symoens S, Nampoothiri S, Gould DB, Baumann U, Bächinger HP, Malfait F

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions.

Scientific reports

Ishikawa Y, Mizuno N, Holden P, Lim PJ, Gould DB, Rohrbach M, Giunta C, Bächinger HP

COL4A1 Mutations Cause Neuromuscular Disease with Tissue-Specific Mechanistic Heterogeneity.

American journal of human genetics

Labelle-Dumais C, Schuitema V, Hayashi G, Hoff K, Gong W, Dao DQ, Ullian EM, Oishi P, Margeta M, Gould DB

Use of sodium 4-phenylbutyrate to define therapeutic parameters for reducing intracerebral hemorrhage and myopathy in Col4a1 mutant mice.

Disease models & mechanisms

Hayashi G, Labelle-Dumais C, Gould DB

Assessing the impact of the Graduate Certificate in Anatomical Sciences Instruction: A post-degree survey.

Anatomical sciences education

Richardson-Hatcher A, MacPherson B, Gould D, Brueckner-Collins J

Mutations of conserved non-coding elements of PITX2 in patients with ocular dysgenesis and developmental glaucoma.

Human molecular genetics

Protas ME, Weh E, Footz T, Kasberger J, Baraban SC, Levin AV, Katz LJ, Ritch R, Walter MA, Semina EV, Gould DB

Characterization of a variant of gap junction protein α8 identified in a family with hereditary cataract.

PloS one

Kuo DS, Sokol JT, Minogue PJ, Berthoud VM, Slavotinek AM, Beyer EC, Gould DB

Genetic dissection of anterior segment dysgenesis caused by a Col4a1 mutation in mouse.

Disease models & mechanisms

Mao M, Kiss M, Ou Y, Gould DB

"Small Blood Vessels: Big Health Problems?": Scientific Recommendations of the National Institutes of Health Workshop.

Journal of the American Heart Association

Bosetti F, Galis ZS, Bynoe MS, Charette M, Cipolla MJ, Del Zoppo GJ, Gould D, Hatsukami TS, Jones TL, Koenig JI, Lutty GA, Maric-Bilkan C, Stevens T, Tolunay HE, Koroshetz W, “Small Blood Vessels: Big Health Problems” Workshop Participants

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations.

Matrix biology : journal of the International Society for Matrix Biology

Jeanne M, Gould DB

Erratum to: Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation.

BMC biology

Loscertales M, Nicolaou F, Jeanne M, Longoni M, Gould DB, Sun Y, Maalouf FI, Nagy N, Donahoe PK

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

The Journal of clinical investigation

Proekt I, Miller CN, Jeanne M, Fasano KJ, Moon JJ, Lowell CA, Gould DB, Anderson MS, DeFranco AL

Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation.

BMC biology

Loscertales M, Nicolaou F, Jeanne M, Longoni M, Gould DB, Sun Y, Maalouf FI, Nagy N, Donahoe PK

Triggering of organ-specific autoimmunity through synergy of defects in key tolerance checkpoints.

The Journal of Immunology

Irina Proekt, Corey Miller, Marion Jeanne, Kayla Fasano, Clifford A Lowell, Douglas Gould, Mark S Anderson, Anthony L DeFranco

Col4a1 mutations cause progressive retinal neovascular defects and retinopathy.

Scientific reports

Alavi MV, Mao M, Pawlikowski BT, Kvezereli M, Duncan JL, Libby RT, John SW, Gould DB

Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms.

Current topics in membranes

Mao M, Alavi MV, Labelle-Dumais C, Gould DB

A Transcriptomic Analysis of Cave, Surface, and Hybrid Isopod Crustaceans of the Species Asellus aquaticus.

PloS one

Stahl BA, Gross JB, Speiser DI, Oakley TH, Patel NH, Gould DB, Protas ME

In Vivo Visualization of Endoplasmic Reticulum Stress in the Retina Using the ERAI Reporter Mouse.

Investigative ophthalmology & visual science

Alavi MV, Chiang WC, Kroeger H, Yasumura D, Matthes MT, Iwawaki T, LaVail MM, Gould DB, Lin JH

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma in Col4a1 Mutant Mice.

Investigative ophthalmology & visual science

Mao M, Smith RS, Alavi MV, Marchant JK, Cosma M, Libby RT, John SW, Gould DB

In vivo longitudinal assessment of cellular processes using fluorescence reporters.

Mitochondrion

Marcel V. Alavi, Douglas B. Gould

Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention.

Circulation

Jeanne M, Jorgensen J, Gould DB

Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.

Cell

Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schürer SC, Snapp EL, Gould DB, German MS, Backes BJ, Maly DJ, Oakes SA, Papa FR

Spontaneous development of autoimmune uveitis Is CCR2 dependent.

The American journal of pathology

Chen YF, Zhou D, Metzger T, Gallup M, Jeanne M, Gould DB, Anderson MS, McNamara NA

Collagen XVIII short isoform is critical for retinal vascularization, and overexpression of the Tsp-1 domain affects eye growth and cataract formation.

Investigative ophthalmology & visual science

Aikio M, Hurskainen M, Brideau G, Hägg P, Sormunen R, Heljasvaara R, Gould DB, Pihlajaniemi T

Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by Col4a1 and Col4a2 mutations.

Human molecular genetics

Kuo DS, Labelle-Dumais C, Mao M, Jeanne M, Kauffman WB, Allen J, Favor J, Gould DB

COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets.

Human molecular genetics

Kuo DS, Labelle-Dumais C, Gould DB

COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage.

Annals of neurology

Weng YC, Sonni A, Labelle-Dumais C, de Leau M, Kauffman WB, Jeanne M, Biffi A, Greenberg SM, Rosand J, Gould DB

COL4A2 mutation associated with familial porencephaly and small-vessel disease.

European journal of human genetics : EJHG

Verbeek E, Meuwissen ME, Verheijen FW, Govaert PP, Licht DJ, Kuo DS, Poulton CJ, Schot R, Lequin MH, Dudink J, Halley DJ, de Coo RI, den Hollander JC, Oegema R, Gould DB, Mancini GM

Abstract 3665: COL4A1 and COL4A2 Mutations cause Genetically Modifiable Cerebrovascular Diseases.

Stroke

Marion Jeanne, Yi-Chinn Weng, Michelle de Leau, Cassandre Labelle-Dumais, Berkeley W Kauffman, Steven M Greenberg, Jonathan Rosand, Douglas B Gould

COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.

American journal of human genetics

Jeanne M, Labelle-Dumais C, Jorgensen J, Kauffman WB, Mancini GM, Favor J, Valant V, Greenberg SM, Rosand J, Gould DB

COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans.

PLoS genetics

Labelle-Dumais C, Dilworth DJ, Harrington EP, de Leau M, Lyons D, Kabaeva Z, Manzini MC, Dobyns WB, Walsh CA, Michele DE, Gould DB

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.

Journal of medical genetics

Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M

A male with unilateral microphthalmia reveals a role for TMX3 in eye development.

PloS one

Chao R, Nevin L, Agarwal P, Riemer J, Bai X, Delaney A, Akana M, JimenezLopez N, Bardakjian T, Schneider A, Chassaing N, Schorderet DF, FitzPatrick D, Kwok PY, Ellgaard L, Gould DB, Zhang Y, Malicki J, Baier H, Slavotinek A