PI | Yamamoto Lab@BCM

I was originally trained as a veterinarian at the University of Tokyo Veterinary Medical School, and also gained three years of research experience during this DVM training. The first set of model organisms I worked with were goats and sheep, which are used as models to study molecular mechanisms of pregnancy in ruminants (e.g. cattle). Next, I used mice to study molecular mechanisms of implantation during pregnancy, early embryogenesis, and inflammatory bowel diseases. While I became fascinated in biomedical research through these experiences, I also learned the challenges and limitations in working with mammalian model organisms.

After obtaining my BS and DVM degrees in Japan, I moved to the US and joined the Program of Developmental Biology at Baylor College of Medicine (BCM) to pursue basic research using a more genetically trackable model organism towards my PhD. I joined the laboratory of Dr. Hugo J. Bellen, who is one of the most charismatic and influential fruit fly (Drosophila melanogaster) geneticists. In his laboratory, I designed and led a large forward genetic screen on the Drosophila X-chromosome to isolate thousands of mutations in essential genes that are involved in proper development, function, or maintenance of the nervous system. Through detailed phenotypic characterization and further molecular and cell biological analyses, our team of graduate students, postdocs and technicians have successfully uncovered novel regulatory mechanisms underlying Notch signaling, Hedgehog signaling, central and peripheral nervous system development, phototransduction, and neurodegeneration. Many of these studies have direct relevance to human diseases.

By combining my strengths in Drosophila research with my earlier training and research experience in veterinary medicine and mammalian biology, I was fortunate to 'skip-a-postdoc' and obtained an independent position in 2013 as a Fellow of the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital (TCH) through Dr. Huda Zoghbi's enormous support and encouragement. I was promoted to a tenure-track Assistant Professor in the Department of Molecular & Human Genetics at BCM in 2017, and also obtained a secondary appointment in the Department of Neuroscience. I actively participate in three PhD programs at BCM [Genetics & Genomics, Neuroscience, and DDMT (Development, Disease Models & Therapeutics)], and run an vibrant basic/translational research laboratory that studies various topics related to the nervous system using state-of-the-art Drosophila genetic technologies.

Many projects in my lab are related to rare and undiagnosed diseases. In fact, >25 million individuals (about the population of Texas) are affected by rare or ultra-rare diseases in the US alone. This number is more staggering at the global scale (affecting >300 million people worldwide, which is about the population of the US), and many experience a long and winding 'diagnostic odyssey' to try to find out the cause of their disorders. While state-of-the-art genomic technologies such as whole-exome sequencing (WES) and whole-genome sequencing (WGS) may provide answers to a subset of these individuals, many are often left with a handful of candidate genetic variants that require experimental studies to understand their functional consequences. As a co-director/co-lead of the Model Organisms Screening Center (MOSC) of the Undiagnosed Diseases Network (UDN) and BCM Center for Precision Medicine Models (CPMM), my lab utilizes Drosophila to test whether a genetic variant identified in a patient is the cause of their disease, which is pursued in close collaboration with clinicians and human geneticists across the country and around the world. I am also a member of the recently established BCM Undiagnosed Disease Center (UDC), a clinical/research initiative at BCM to support patients and families who are struggling to receive an accurate diagnosis. In collaboration with bioinformaticians and programmers at BCM/NRI (Dr. Zhandong Liu's lab), I am also involved in the development of novel computational tools such as MARRVEL and ModelMatcher to facilitate rare disease diagnosis, research, and collaborations on a global scale. Over the years, my interest has expanded to include more common neurological disorders such as autism spectrum disorders (ASD), Alzheimer's disease, psychiatric diseases and drug addiction. More recently, we are also developing creative strategies to study infectious diseases such as Zika virus mediated microcephaly and COVID-19, given their socioeconomic importance.

In summary, while members of my lab and I work on diverse research topics, all projects are built on a common foundation that harnesses the 'awesome power of fly genetics'.

Funding

Current Support

U54 OD030165 (NIH ORIP) Heaney/Lee/Milosavljevic (PD/PI) 9/15/2020-9/14/2025

The major goal of this project is to establish a BCM Center for Precision Medicine Models, which will support local, national, and international programs and individual researchers in the development of precision animal models that end the diagnostic odyssey of patients with undiagnosed, rare, and Mendelian diseases and serve as resources for pre-clinical studies investigating personalized medicine approaches to their care.

Role: Co-I of the whole proposal, and Project Co-Lead of Resource and Services Section

RF1 AG071557 (NIH NIA) Yamamoto (PD/PI) 5/1/2021-4/30/2026

The major goal of this proposal is to study the function of TM2D3 and its related genes in the context of Alzheimer’s disease pathogenesis in Notch signaling.

Role: PD/PI

R01 HG011795 (NIH NHGRI) Bellen/Wangler (PD/PI) 7/13/2021-4/30/2026

The major goal of this project is to facilitate the implementation of genomic medicine in a medically underserved population by combining the latest clinical diagnostics, bioinformatics and Drosophila genetics tools in a clinical setting.

Role: Co-I

#2023-32824 (Chan Zuckerberg Initiative) Gibbs/King/Bellen (PD/PI) 08/01/2023-07/31/2027

The major goal of this subcontract is to provide diagnosis and study mechanisms of rare undiagnosed pediatric disorders at Texas Children’s Hospital.

Role: Co-I

#2023-332162 (Chan Zuckerberg Initiative) Yamamoto (PD/PI) 11/01/2023-10/31/2025

The major goal of this grant is to further develop MARRVEL, AI-MARRVEL and ModelMatcher to facilitate diagnosis and collaborative research for rare diseases.

Role: PI

Mark A. Wallace Endowment Award (Texas Children’s Hospital) Yamamoto/Zoghbi (PIs) 7/1/2025-6/30/2026

This internal funding is used to study the role of KCJN2 in psychiatric diseases using Drosophila.

Role: PI

Raynor Funds (Texas Children’s Hospital) Yamamoto (PI) 7/1/2025-6/30/2026

This philanthropic fund is used to support functional studies in Drosophila to study variants and genes of uncertain significance found in patients with rare and undiagnosed diseases.

Role: PI

R21OD038417 (NIH ORIP) Yamamoto (PD/PI) 7/15/2025-6/30/2027

The major goal of this project is to sequence and map ~700 EMS-induced lethal mutants on the Drosophila X-chromosome using the state-of-the-art-genomic and genetic technology. These mutants were left unmapped from the X-chromosome screen project (Yamamoto et al., 2014) and this collection is known to be enriched for mutants that affect evolutionarily conserved genes that are linked to rare diseases in human.

Role: PD/PI

Past Support

Nakajima Foundation Fellowship (Nakajima Foundation) Yamamoto (Fellow) 5/1/2005-4/30/2010

This competitive fellowship is awarded to 3-4 Japanese students annually to pursue graduate studies in the life science field in a foreign country. Fellows receive a generous stipend for 5 years.

Role: Pre-Doctoral Fellow

NRI Fellowship (Texas Children’s Hospital) Yamamoto (PI) 3/1/2013-2/28/2017

The NRI Fellowship is designed to recruit and support candidates that have just received their final degrees (Ph.D.) to start up an independent laboratory at the Jan and Dan Duncan Neurological Research Institute (NRI) at TCH. This support was used to perform a forward genetic screen to identify new genes involved in Dopamine synthesis, secretion, and metabolism in Drosophila.

Role: PI

R13 HD080297-01 (NIH NCI & NICHD) Blacklow (PI) 5/10/2014-4/30/2015

This grant supported a Gordon Research Conference (GRC) and Seminar (GRS) on “Notch Signaling in Development, Regeneration & Disease” held in July 19-25, 2014 at Bates College, Maine.

Role: Chair of GRS

Targeted-Functional Screen of Autism-Associated Variants Award (Simons Foundation) Wangler/Yamamoto (PIs) 8/1/2015-7/31/2018

The major goal of this project is to perform functional analyses of rare variants in conserved Autism genes found in the Simons Simplex Cohort using Drosophila.

Role: Co-PI

U54 NS093793 (NIH NINDS & CommonFund) Bellen (PD/PI) 9/15/2015-6/30/2023

The major goal of this project is to establish and operate a Model Organisms Screening Center (MOSC) that will provide valuable in vivo functional information of conserved genes that are likely to be involved in rare human diseases by performing genetic experiments in Drosophila and Zebrafish as part of the larger Undiagnosed Disease Network (UDN).

Role: Co-I of overall, Project Lead of Drosophila Core

New Investigator Research Grant (Alzheimer’s Association) Yamamoto (PI) 10/1/2015-9/30/2017

The major goal of this project is to understand the functional effect of a late-onset Alzheimer’s disease associated variant in TM2D3 using Drosophila.

Role: PI.

R24 OD022005 (NIH ORIP) Bellen (PD/PI) 06/01/2016 - 05/31/2025 (NCE)

The goal of this study is to generate a large library of human cDNA expressing constructs and transgenic Drosophila strains to facilitate the use of fruit flies in biomedical research.

Role: Co-I

R01 DC014932 (NIH NIDCD) Groves (PI) 12/1/2016-11/30/2022

The goal of this proposal is to study the role of the ubr3 gene in regulating proteins involved in usher syndrome, the most common form of deaf-blindness, and myh9-related disease syndromes that can also cause deafness. In addition, we will perform genetic screens to identify additional genes involved in hearing in insects and mice.

Role: Co-I

Junior Faculty Seed Funding Award (Naman Family Fund for Basic Research and Caroline Wiess Law Fund for Research in Molecular Medicine, Baylor College of Medicine) Yamamoto (PI) 07/01/2017-06/30/2018

The major goal of this project is to understand the function of proteins and non-coding RNAs encoded in the Zika viral genome using Drosophila to understand the mechanism by which this virus cause microcephaly in humans.

Role: PI

Nancy Chang, Ph.D. Award for Research Excellence (Baylor College of Medicine) Yamamoto (PI) 07/01/2019-06/30/2020

The major goal of this project is to understand the function of TM2D family proteins in the context of Notch signaling and late-onset Alzheimer’s disease using Drosophila.

Role: PI

U01 HG007530-07 subaward (NIH NHGRI) Kohane/McCray/Might (PD/PI) 7/1/2020-6/30/2021

The major goal of this administrative supplement is to study the function of GLS, a gene identified as a in the Undiagnosed Disease Network as a disease-causing gene, using Drosophila.

Role: Project Lead

U54 NS093793-06S1 (NIH NINDS) Bellen (PD/PI) 7/01/2020-6/30/2021

The major goal of this administrative supplement is to establish a global matchmaking system between scientist and clinicians called ModelMatcher to facilitate rare and undiagnosed disease research.

Role: Project Lead

R24 OD022005-05S1 (NIH ORIP) Bellen (PD/PI) 07/01/2020 - 06/30/2022

The major goal of this administrative supplement is to establish a genetic tool kit of SARS-CoV-2 and human cDNAs to study the functional interaction of host-protein proteins involved in COVID-19.

Role: Co-I

U54 NS093793-07S1 (NIH NINDS) Bellen (PD/PI) 7/01/2021-6/30/2022

The major goal of this administrative supplement is to increase the utility of MARRVEL and ModelMatcher by integrating these two online resources to facilitate rare and undiagnosed disease research.

Role: Project Lead

Research Award (SATB2 Gene Foundation) Yamamoto (PD/PI) 12/1/2021-2/28/2023

The major goal of this project is to study the function of pathogenic variants identified in SATB2-associated syndrome and to further functionally characterize the role of this gene in the nervous system using Drosophila.

Role: PI

R24 OD022005-07S1 (ORIP) Bellen (PD/PI) 06/01/2022-05/31/2025

The major goal of this administrative supplement is to expand and characterize a genetic tool kit of SARS-CoV-2 and human cDNAs to study the functional interaction of host-protein proteins involved in COVID-19.

Role: Co-I

U54 NS093793-07S2 (NIH NINDS & CommonFund) Bellen (PD/PI) 7/1/2022-6/30/2023

The major goal of this project is to continue to perform genetic experiments in Drosophila and Zebrafish in the Model Organisms Screening Center (MOSC) to support the mission of the larger Undiagnosed Disease Network (UDN).

Role: Co-I of overall, Project Lead of Drosophila Core

U2C NS132415-01S01 subaward (NIH NINDS) Kohane/Ashley/Marth/Might/Taylor/Warner (PD/PI) 07/01/2023-03/31/2024

The major goal of this subcontract is to pursue functional studies in Drosophila to support the diagnostic mission of the Phase III UDN.

Role: Co-I

U2C NS132415-02S01 subaward (NIH NINDS) Kohane/Ashley/Marth/Might/Taylor/Warner (PD/PI) 06/01/2024-03/31/2025

The major goal of this subcontract is to pursue functional studies in Drosophila to support the diagnostic mission of the Phase III UDN.

Role: Co-I