Protecting the Heart from Chemotherapeutic Damage Using Engineered TAFAZZIN

Supervisor: Dr. Michael Chin, Tufts University School of Medicine

Project Background

Some of the most effective cancer treatments also come with serious side effects. One
widely used chemotherapy drug, doxorubicin, is very successful at treating cancer, but it
can damage the heart when patients receive high or repeated doses. This heart damage
can limit how much treatment a patient can safely receive and can affect quality of life long
after cancer treatment ends.

This project focuses on finding ways to protect the heart without reducing the effectiveness
of cancer therapy. I am studying a naturally occurring protein called TAFAZZIN, which plays
an important role in keeping heart cells healthy by supporting how they produce energy.
When this protein does not function properly, as seen in a rare condition called Barth
Syndrome, the heart muscle becomes weak. This suggests that TAFAZZIN is essential for
maintaining heart health, especially under stress.

Research Question

Through my research, I will answer the question: does concurrent administration of
TAFAZZIN, engineered to contain a cell penetrating peptide, with the anti-cancer drug
doxorubicin, reduce doxorubicin-induced cardiotoxicity by preserving mitochondrial
integrity and reducing heart cell death?

Methodology

My project will investigate whether TAFAZZIN, delivered with a cell-penetrating modification
to allow uptake by cells, can reduce doxorubicin-induced heart cell injury. I will work with
three types of H9C2 heart cells: normal (wild-type) cells, cells engineered to produce extra
TAFAZZIN after exposure to doxorubicin, and cells that lack TAFAZZIN entirely. Each cell
type will be divided into four experimental groups: an untreated control group, a group
treated with doxorubicin alone, a group with TAFAZZIN enzyme replacement therapy alone,
and a group receiving both TAFAZZIN enzyme replacement therapy and doxorubicin at the
same time.

Heart cells treated with doxorubicin will be monitored over a 24-, 48-, and 72-hour time
course to assess whether TAFAZZIN delays or prevents cell death. Cell survival and death
will be measured using Annexin V staining and flow cytometry, providing a quantifiable
readout of apoptosis. To understand the cellular mechanisms underlying any protective
effects, I will also measure autophagic flux, a process that helps cells maintain healthy
mitochondria and is known to be disrupted by doxorubicin. Autophagy will be assessed
both through protein analysis by western blot and by autophagy-specific fluorescent
probes.

By comparing outcomes across all cell types and treatment groups, I aim to determine
whether TAFAZZIN can preserve mitochondrial function and improve cell survival in the
context of doxorubicin exposure. This work will not only provide insight into potential
cardioprotective strategies but also help identify mechanisms by which mitochondrial
stabilization can mitigate chemotherapy-induced stress.

This project will be conducted in collaboration with the cardio-oncology research group at
Tufts Medical Center, allowing me to work alongside both basic scientists and clinicians.
This connection emphasizes the real-world relevance of the research and highlights how
laboratory findings can inform clinical care. 

Goals and Outcomes

Through this project, I hope to gain experience independently designing, executing, and analyzing a research study. Since I have never conducted independent research before, it would be especially meaningful for me to take charge of my own project. The nature of this project will allow me to translate scientific findings toward clinically relevant questions, preparing me for a future career at the intersection of medical research and patient care. I also hope to learn to interpret unexpected results and communicate scientific findings to diverse audiences. With a strong interest in cardiology, I look forward to gaining a deeper understanding of mitochondrial dysfunction and cardiotoxicity in the context of cancer treatment. 

Ultimately, this project seeks to improve our understanding of how mitochondrial stabilization may protect the heart during chemotherapy. If successful, it could contribute to the development of interventions that allow patients to receive effective cancer treatment with reduced risk of long-term cardiac complications, moving toward safer, more targeted therapies for cancer patients.