# Modeling Reciprocal Genomic Disorders in Neuronal Cells and Cerebral Organoids

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $110,380

## Abstract

Abstract
The proposed research and training program will prepare Dr. Xander Nuttle to become an independent
investigator focused on human genetics and neurodevelopmental genomics. Dr. Nuttle obtained a Ph.D. in
Genome Sciences, investigating genes specifically duplicated along the human lineage, and has dedicated his
postdoctoral training to the development of innovative methods of genome engineering in relation to human
reciprocal genomic disorders (RGDs). He now seeks to develop new expertise in functional genomics by
leveraging emerging stem-cell, single-cell, organoid, and genome engineering technologies to characterize
mutations linked to neurodevelopmental disorders. The training program consists of two phases: two years
acquiring new skills primarily through mentored research, followed by three years establishing an independent
laboratory.
 The research plan incorporates both experimental and computational approaches, modeling RGDs in
neuronal cells and cerebral organoids to gain insights into mechanisms of pathogenesis. Dr. Michael
Talkowski, Associate Professor of Neurology at the Center for Genomic Medicine (CGM) at Massachusetts
General Hospital (MGH), will serve as the primary mentor. Dr. Kevin Eggan, Professor of Stem Cell and
Regenerative Biology at Harvard University, will provide complementary expertise as a co-mentor. The mentor
and co-mentor are world leaders in psychiatric genetics, functional genomics, and cellular disease modeling.
To supplement their mentorship, a team of investigators at various career stages will provide Dr. Nuttle with
targeted training and career development advice. The CGM at MGH, Harvard, and the Broad Institute form a
highly collaborative environment ideally positioned to support Dr. Nuttle’s transition to independence. Here, he
will have access to abundant resources and tools and a wealth of diverse scientific and clinical expertise.
 RGDs are among the most common genetic subtypes of autism spectrum disorder, schizophrenia,
bipolar disorder, attention-deficit/hyperactivity disorder, and intellectual disability. All RGDs involve recurrent
deletions and duplications of particular genomic segments, yet the molecular details of how these dosage
changes confer disease are not well understood. To address this challenge, we will (1) examine transcriptional
signatures and neurite dynamics in RGD neuronal cellular models; (2) generate and characterize RGD
cerebral organoid models; and (3) integrate high-throughput genome engineering with cellular modeling to
identify driver genes underlying RGD-associated neurite phenotypes. This research will immerse Dr. Nuttle in
several cutting-edge fields, giving him the opportunity to learn functional genomics, single-cell analysis, and
brain organoid modeling. With these skills in hand, he will be able to functionally characterize genetic variation
affecting neurodevelopment and be well-positioned to launch a productive independent research program.

## Key facts

- **NIH application ID:** 10127264
- **Project number:** 1K99MH121577-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Xander Nuttle
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $110,380
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127264

## Citation

> US National Institutes of Health, RePORTER application 10127264, Modeling Reciprocal Genomic Disorders in Neuronal Cells and Cerebral Organoids (1K99MH121577-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127264. Licensed CC0.

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