TL1 Postdoctoral Trainee Spotlight Brittany Martinez, Ph.D., University of Kansas Medical Center

Project Title: Investigating the molecular mechanism of cleft palate rescue in Thm1 heterozygous female mice

Project Summary: Annually 3,000 children are born in the United States with craniofacial anomalies, which include clefts of the lip and palate. These children endure multiple surgeries along with speech and language therapy, which can cost >$100,000/child. The mechanisms which underlie syndromic and isolated phenotypes are not well understood due to their complex etiology. While there is evidence that smoking and folate metabolism are known to affect the maternal environment, little is known about how maternal genetics can affect the development of these birth defects. Here we present a novel model system which protects against cleft palate (CP), the first of it’s kind. Our model was serendipitously discovered when investigating the genetic interaction between cytoskeletal Specc1l and ciliary Thm1. Homozygous mutants of these two genes share overlapping phenotypes including cleft palate, exencephaly, and shortened primary cilia. Due to these overlapping phenotypes, we investigated if these two genes genetically interact. Indeed, we found a novel genetic interaction between these two genes as double heterozygotes show increased penetrance of cleft palate at 34%, with the single heterozygote counterparts Specc1l^∆CCD2/+ showing 18% and Thm1^-/+ demonstrating 0% cleft palate, respectively. This only occurs when the mother is Specc1l^∆CCD2/+ and the father is Thm1^-/+, when genotypes are reserved, no CP is observed in single or double heterozygous embryos. Using control crosses, we have identified Thm1^-/+, maternal environment to be protective against cleft palate. The objective of this proposal is to study the protective maternal genetic effect of Thm1 heterozygosity on CP and uncover the changes in Thm1^+/- female uterus tissue that leads to rescue of CP. We hypothesize that Thm1 heterozygosity leads to changes in maternal uterine tissue that positively influence the fetus. In this proposal, I will validate these findings in the uterus and identify the molecular consequences in the embryo that lead to CP rescue, with the following two aims: Aim 1) Investigate mTOR-AKT axis and response to nutrients in Thm1^+/- females and human placenta tissue. Aim 2) Determine the molecular basis of palate closure in Thm1^+/-  females and establish timing of palate closure in humans. This work offers novel findings associated with the development of CP and therefore the potential for therapeutic strategies in the development of cleft palate.

Mentors: Irfan Saadi, PhD and Pamela V. Tran, PhD

The reason people apply for the Frontiers TL1 program varies as much as the topics they research, and Brittany Martinez, Ph.D., is no different.

“I saw the project I’m working on start to take a translational turn and my mentor, and I thought applying for the TL1 program would be really good,” she said. “Frontiers offers a lot of opportunities, and we thought it would be good for me to be exposed to people who are already doing translational research.”

Martinez came across a novel mouse model that protects against cleft palate during her Ph.D. training while interrogating the genetic interaction between  cytoskeletal gene (Specc1l) and ciliary  gene (Thm1). She found these genes do in fact interact and lead to  increased penetrance of cleft palate.

“What was interesting is that we found this genetic interaction only occurred when the mother was heterozygous for Specc1l,” she said. “When we switched the genotypes of the parents and used a Thm1 heterozygous mother, we found no cleft palate. This was exciting and interesting because such a rescue does not normally happen.”

As the project progresses, Martinez is focusing on how nutrients are impacting this protective effect.

“We found that different nutrient receptors have increased expression in the Thm1 heterozygous uterine tissue, and what we hypothesize is that the Thm1 heterozygous female’s uterine environment is more responsive to nutrients.  These nutrients are important for growth and development, and their increase may be protecting against cleft palate.”

The next steps in Martinez’ project is to study the difference in nutrient availability in the uterus, and then correlate that in the placenta and the embryo to understand what the embryo is sensing.

“At my core, I’ll always be a basic scientist, but ultimately I would like to do more translational research,” she said. “It’s really exciting, and there are so many things we need to understand in a mouse before we take it to humans. And once we understand more about which nutrients are protecting against cleft palate, and perhaps other malformations, we can then start to look at how we can make this beneficial to people.”

Martinez is also glad she applied for the TL1 program because of the various training and opportunities it provides.

“The Center for the Improvement of Mentored Experiences in Research (CIMER) training has been really beneficial and the CliftonStrengths^Ò Leadership Training has been great,” she said. “I’ve experienced some situations where I had to say no to something and the trainings have helped. And I’ve learned why I respond the way I do to some situations so it’s really helped me when I’m faced with challenges to be able to work through them.”

Martinez is happy to hear the feedback from the Frontiers Scholars Club Mentors because they bring a different perspective to the Scholars projects and help them think through how they are presenting their research.

“I’ve really enjoyed the interaction with my peers and hearing about their research in the Frontiers Scholars Club. We all bring something different to the table and I think it’s been really beneficial.”

And if someone was thinking about applying for the TL1 program?

“Just do it,” she said. “Don’t turn down this opportunity because you think it might not be a good fit. The worst thing that will happen is you don’t get selected. But it’s been a great program for me and I would encourage people to apply.” 

And recently, Martinez was selected as a National Trainee Representative for the Clinical and Translational Award (CTSA) programs TL1 Directors and Executive Council. During her term, she will provide insight into the TL1 program and the impact decisions made by the Council and Directors affect TL1 trainees. She’ll also be involved in communications with other TL1 trainees across the country, ensuring accurately and timely communications are sent, and working with the  Dr. H. William Schnaper Visiting Scientist Grand Rounds, Debate Forum and minisymposia with CTSA programs across the country.