The Intramural Research Fellowship (IRF) is a competitive research funding opportunity for NICHD postdoctoral, visiting, and clinical fellows. Its main objective is to promote grant writing among intramural trainees, while enhancing awareness of the various components of an NIH grant application.

Reflecting the breadth of research in the NICHD Division of Intramural Research, the 2024 award-winning projects span the molecular underpinnings of mitosis to system-level influences on the progression of disease. We invite you to learn more about this impactful work, as the four current IRF recipients have graciously shared their research projects below—with a peek into what excites them about their work.

Learn more about what it takes to write a winning grant application from the 2023 IRF award winners: Grant Writing Wisdom from IRF Recipients

Please contact the IRF awardees at the email addresses below to ask additional questions or for a list of publications related to their work:

Aurora Kraus, PhD

Laboratory of Brant Weinstein, PhD, Section on Vertebrate Organogenesis

Aurora Kraus

Aurora Kraus, PhD

Visualizing traumatic brain injury in the adult zebrafish

Many people suffer long-term consequences after head injury, and persistent vascular dysfunction is a contributing factor.1 The goal of this project is to examine immune responses to mild traumatic brain injury and decipher how brain vessels are involved in these immune responses.

We are using zebrafish to perform these studies. The zebrafish is a model organism with a thin, optically clear skull that permits direct, high-resolution microscopic imaging of brain injury sites in living animals. This project establishes zebrafish as an important, comparative model to understand how endothelial and immune cells communicate after injury.

I love microscopy and watching cells interact. The zebrafish is an amazing model for longitudinal, live imaging of the meninges with many transgene reporters, and I am excited to observe putative cell-cell interactions in real-time.


Tanmay Mondal, PhD

Laboratory of Anirban Banerjee, PhD, Section on Structural and Chemical Biology

Tanmay Mondal

Tanmay Mondal, PhD

Development of orthogonal fluorescence-based assays to study substrate S-acylation: A novel direct method

I am developing novel assays for studying protein S-acylation, a widely prevalent form of protein modification whereby lipids are added to proteins by a family of transmembrane enzymes. Protein S-acylation is by far the most common form of protein lipidation2—with 23 zDHHC enzymes catalyzing the S-acylation of nearly 6000 substrates3,4—and has been linked to a wide range of diseases including neurological disorders,5 neuropsychiatric diseases, diabetes, and several forms of cancer.6

To date, there are very few studies investigating substrate S-acylation by zDHHC enzymes using in vitro biochemical methods, and there are no selective inhibitors of zDHHC enzymes. The development of these assays for substrate S-acylation is an unmet need that could provide novel insights into substrate recognition by zDHHC enzymes as well as open up de novo approaches for discovering selective zDHHC inhibitors.

For the development of these fluorescence-based assays, I am using sidechain modified peptide fragments of substrates, which I am synthesizing. Simultaneously, I am developing an orthogonal protein S-acylation assay using click chemistry, a kind of chemical reaction that can be carried out in complex aqueous mixtures, including cellular lysates. These novel assays will help shed light on critically important questions in the field of protein lipidation and will hopefully lead to therapeutic approaches for combating human diseases.


Matthew Manion, PhD

Laboratory of Timothy Petros, PhD, Unit on Cellular and Molecular Neurodevelopment

Matthew Manion

Matthew Manion, PhD

Differential activity of the transcription factor Nkx2.1 in embryonic mouse brain, lung, and thyroid

The transcription factor Nkx2.1 is critical for development of the lung, thyroid and brain, 7–14 and humans with certain NKX2.1 variants have altered function of these three organs.7–10 One outstanding question in developmental biology is how a single transcription factor regulates distinct gene pathways in different tissues during development. Nkx2.1 represents an excellent opportunity to study this phenomenon in more detail.

My project uses sequencing data to compare gene expression and regulatory factors in the developing brain, lung, and thyroid to understand how Nkx2.1 regulates different gene cascades of each of these organs. We believe that this type of study represents a critical step forward for understanding normal development of the brain and other organs, and how perturbations in gene regulation contribute to physical and neurological conditions. 

I come from a neuroscience background. I was drawn to this line of research because it relates to developmental neuroscience, but it also expands out into development of other organs, and I was intrigued by the idea of gene regulatory factors common to organs as different as the brain, lungs, and thyroid.


Sanjana Sundararajan, PhD

Laboratory of Mary Dasso, PhD, Section on Cell Cycle Regulation

Sanjana Sundararajan

Sanjana Sundararajan, PhD

Spindle Assembly Checkpoint Proteins at Interphase Nuclear Pores

The Spindle Assembly Checkpoint (SAC) is a safety mechanism activated by cells during chromosome segregation and is silenced only when all sister chromatids are correctly attached to the mitotic spindle; SAC therefore prevents premature chromosome segregation and ensures mitotic fidelity.15,16 Despite the evolutionarily conserved localization of SAC proteins to interphase Nuclear Pore Complexes (NPCs),17–20 their significance there remains surprisingly unexplored.

Accurate chromosome segregation during cell division is imperative for maintenance of genomic stability and to prevent developmental disorders and cancer. My project aims to delineate how SAC proteins are bound at NPCs and identify their roles prior to mitosis at these channels. This will elucidate why these proteins are stationed at pores in such an evolutionarily conserved manner and expand upon our understanding of how events prior to mitosis contribute to genomic stability.

This research blends my love for studying chromosome segregation and my keen interest for understanding mechanisms that orchestrate the cell cycle!


Footnotes

1 Griffin AD, et al. (2019). Traumatic microbleeds suggest vascular injury and predict disability in traumatic brain injury. Brain 142(11):3550–3564.

2 Jiang H, et al. (2018). Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies. Chemical Reviews 118(3):919–988.

3 Stix R, Lee CJ, Faraldo-Gomez JD, Banerjee B. (2020). Structure and Mechanism of DHHC Protein Acyltransferases. Journal of Molecular Biology 432(18):4983–4998.

4 Malgapo MIP, Linder ME. (2021). Substrate recruitment by zDHHC protein acyltransferases. Open Biol 11(4):210026.

5 Cho E, Park M. (2016). Palmitoylation in Alzheimer's disease and other neurodegenerative diseases. Pharmacol Res 111:133–151.

6 Lobo S, in Unravelling Cancer Signaling Pathways: A Multidisciplinary Approach. (2019), Chapter 3, p. 51–87.

7 Krude H, et al. (2002). Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 109(4):475–480.

8 Kusakabe T, et al. (2006). Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid. Mol Endocrinol 20(8):1796–1809.

9 Guan L, et al. (2021). Thyroid Transcription Factor-1: Structure, Expression, Function and Its Relationship with Disease. BioMed Res. Int., 2021:9957209.

10 Mu D. (2013). The complexity of thyroid transcription factor 1 with both pro- and anti-oncogenic activities. J Biol Chem 288(35):24992–25000.

11 Orquera DP, et al. (2018). NKX2.1 is critical for melanocortin neuron identity, hypothalamic Pomc expression and body weight. bioRxiv 460501. Preprint at https://doi.org/10.1101/460501.

12 Orquera DP, et al. (2019). The Homeodomain Transcription Factor NKX2.1 Is Essential for the Early Specification of Melanocortin Neuron Identity and Activates Pomc Expression in the Developing Hypothalamus. J Neurosci 39(21):4023–4035.

13 Kimura S, et al. (1996). The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev 10(1):60–69.

14 Minoo P, Su G, Drum H, Bringas P, and Kimura S. (1999). Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos Dev Biol 209(1):60–71.

15 Foley EA and Kapoor TM. (2013). Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat Rev Mol Cell Biol 14(1):25–37.

16 Musacchio A and Salmon ED. (2007). The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8(5):379–93.

17 Campbell MS, Chan GK, and Yen TJ. (2001). Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase. J Cell Sci 114(Pt 5):953–63.

18 Lee SH, et al. (2008). Tpr directly binds to Mad1 and Mad2 and is important for the Mad1-Mad2-mediated mitotic spindle checkpoint. Genes Dev 22(21):2926–31.

19 Lince-Faria M, et al. (2009). Spatiotemporal control of mitosis by the conserved spindle matrix protein Megator. J Cell Biol 184(5):647–57.

20 Scott RJ, et al. (2005) Interactions between Mad1p and the nuclear transport machinery in the yeast Saccharomyces cerevisiae. Mol Biol Cell 16(9):4362–74.