Research Experience

Stress response signaling as a metabolic sensor for reproduction

Reproduction is a systemic decision that relies on nutrient availability to support the high energetic cost of gametogenesis and reproductive behaviors. Disorders that yield insufficient/excess body fat mass are associated with decreased ovulation and infertility. In the Fly Stress Lab (led by Dr. Deepika Vasudevan), we have identified the Integrated Stress Response (ISR) as a molecular link between nutrient status and reproductive status. Interestingly, these signaling events originate in the fat body, a liver-like adipose tissue in Drosophila, and influence the yolk lipoprotein content of maturing oocytes (Grmai et al. 2024, Cell Reports). I am utilizing genetic and biochemical methods to characterize transcriptional regulation by the ISR in the fat body under homeostatic and stress conditions.

In addition, we have discovered that loss of ISR factors in fat tissue alter the neuronal control of egg-laying behavior. We found that neuropeptide production downstream of ATF4, the transcriptional effector of the ISR, is required in the fat tissue to ensure egg-laying. Thus, I am also investigating the neuronal control of reproductive behaviors by the ISR. To this end, in collaboration with the Duke CPNE (led by Dr. Kafui Dzirasa) I am adapting a novel neural editing system called LinCx for use in Drosophila systems.

Grmai L, Michaca M, Lackner E, Nampoothiri V.P. N, Vasudevan D (2024). Integrated Stress Response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation. Cell Reports. PMID: 38457339
*an earlier version is viewable on bioRxiv: doi: 10.1101/2023.02.27.530289. PMID: 36909541

Cooperation between sexual identity and steroid hormone signaling in gonad establishment

In the lab of Dr. Mark Van Doren at JHU, I dissected the role of steroid hormone signaling in Drosophila gonads. We determined that Drosophila steroid hormone signaling and Ecdysone receptor (EcR) are female-specific in the early gonad despite high levels of circulating ecdysone in both sexes. Amazingly, I found that EcR and the transcription factor Chinmo (see section below) are mutually repressive in the gonad and thus, gametogenesis in both sexes requires mutually exclusive transcriptional programs in the ovary and testis (Grmai et al. 2023).

Grmai L, Jimenez E, Baxter E, Van Doren M (2023). Sexual identity controls steroid hormone signaling during gonad niche development. bioRxiv. doi: 10.1101/2023.12.22.573099. PMID: 38187640

Grmai L, Pozmanter C, Van Doren M (2022). The role of Sxl in Drosophila germline sexual identity instruction. Sexual Development. PMID: 35259743

Investigating the role of Chinmo in maintenance of spermatogenesis.

My doctoral thesis described the role for the transcription factor Chinmo in preserving male fertility in Drosophila, revealing a novel mechanism for sex maintenance in the adult. In the lab of Dr. Erika Bach at NYU School of Medicine, I developed a method for purifying rare somatic stem cells from testes to identify Chinmo- regulated gene networks. Through transcriptomic analysis of control and Chinmo-deficient somatic stem cells, I identified several candidate Chinmo targets that inform sexual identity of the somatic gonad (Grmai, Harsh et al. 2021). I demonstrated that Chinmo protects male sex identity in the gonad by preventing transcription and alternative splicing of the female sex determinant Transformer, representing novel mechanisms of sexual identity regulation that may be required in other adult tissues (Grmai et al. 2018).

Grmai L, Hudry B, Miguel-Aliaga I, Bach EA (2018). Chinmo prevents transformer alternative splicing to maintain male sex identity. PLOS Genetics. PMID: 29389999

Grmai L*, Harsh S*, Lu S, Korman A, Deb IB, Bach EA (2021). Transcriptomic analysis of feminizing somatic stem cells in the Drosophila testis reveals putative downstream effectors of the transcription factor Chinmo. G3. PMID: 33751104
*authors contributed equally

Zoranovic T, Grmai L, Bach EA (2013). Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway. JAK-STAT. PMID: 24069565

Chronic inflammation promotes tumorigenesis in a mouse mammary tumor model

As an undergraduate in the lab of Dr. Suzanne Ostrand-Rosenberg, I worked to elucidate the mechanisms by which myeloid-derived suppressor cells (MDSC) prevent immunotherapy-based breast cancer treatment. MDSC accumulate in the blood at high levels upon tumor inoculation in mice, representing over 90% of leukocytes at 21 days post-injection. We performed proteomic analysis on wildtype MDSC versus MDSC induced in a pro-inflammatory environment; validation of mass spectrometry revealed that pro-inflammatory MDSC accumulate at higher levels than wild type MDSC because they are more resistant to Fas-mediated apoptosis. Specifically, pro-inflammatory MDSC had significantly lower levels of activated Caspase-8 and activated Caspase-3 compared with wildtype MDSC.

Chornoguz O, Grmai L, Sinha P, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S (2011). Proteomic pathway analysis reveals inflammation increases myeloid-derived suppressor cell resistance to apoptosis. Mol Cell Proteomics. PMID: 21191032