Rodney Infante, MD, Ph
- Personal Statement
My research training positions me to investigate lipid metabolism. My graduate school and post-doctoral training detailed the fundamental understanding of intracellular lipid transport between organelles and described the mechanistic defect in the proteins mutated in Niemann-Pick C disease. This body of work detailed how proteins can transfer hydrophobic lipids between each other during intracellular lipid transport. After completing my internal medicine residency at Massachusetts General Hospital, I returned to the University of Texas Southwestern Department of Molecular Genetics and Center of Human Nutrition to study a clinical syndrome with altered lipid metabolism, cancer cachexia (CCX). More specifically, I would like to identify the lipolysis factors secreted by immune and cancer cells that cause adipose tissue wasting and the mechanisms they use in this process. I have collaborated with oncologist Dr. Puneeth Iyengar in the Harold Simmons Comprehensive Center who has both a background in adipocyte/cancer biology with efforts in clinical/translational CCX/cancer research. Our initial studies have already yielded a lipolysis factor that has peripheral and central roles causing significant wasting similar to the CCX phenotype. Using this molecule, we have defined a Tumor-Adipose-Hypothalamic Axis that is regulating CCX. The ultimate goal is to use these pathways for the treatment of CCX. I have actively researched in the field of lipid metabolism for over 8 years using biochemical, molecular biology, structural biology and now in-vivo analysis and feel I have the optimal training and mentorship to detail CCX’s mechanism to identify a durable and efficacious therapy.
- Positions and Honors
Positions and Employment
6/2012-6/2014 Resident, Department of Internal Medicine, Massachusetts General Hospital (MGH), Boston, MA
7/2014-10/2017 Clinical and Research Fellow in Gastroenterology, Department of Internal Medicine, UTSW, Dallas, TX
7/2015-6/2017 Research Fellow, Center of Human Nutrition, UTSW, Dallas, TX
11/2017-Current Assistant Professor, Center of Human Nutrition/Department of Molecular Genetics/Department of Internal Medicine, University of Texas Southwestern Medical Center (UTSW), Dallas, TX
Other Experience and Professional Memberships
American Gastroenterological Association
Texas Medical Association
Dallas County Medical Society
AOA Medical Society
Florida Blue Key
1997 Florida Blue Key, University of Florida.
1997 Highest Honors, University of Florida.
2005 Research Poster Award, Medical Student Research Forum, UTSW
2008 Nominata Award, UTSW Graduate School of Biomedical Sciences.
2008 Ara Parseghian Medical Research Foundation Fellow
2009 Norton B Gilula Award, The American Society for Cell Biology.
2011 Merck Fellow, Medical Scientist Training Program, UTSW
2011 Alpha Omega Alpha Honor Medical Society
2012 Hemphill-Gojer Award, Department of Internal Medicine, UTSW.
2013 Best Intern, Department of Internal Medicine, MGH
2015 Human Nutrition Fellow, UTSW
- Contributions to Science (*; Co-corresponding author)
- Studies Investigating Systems Biology of Cancer Cachexia (CCX).
Recently, our group has generated biologic insight into the development of the wasting syndrome cancer cachexia (CCX). We have created an unbiased CCX in-vitro adipocyte lipolysis assay to determine novel cachexia lipolysis factors. We have identified a colon cancer-secreted IL-6 family member (leukemia inhibitory factor) that induces CCX adipose wasting using in-vitro and in-vivo models. Using this molecule, we have identified both peripheral (adipocyte lipolysis) and central (hypophagia) roles in inducing body weight and adipose loss. With chronic exposure to the CCX factor, leptin levels decrease returning food intake to normal levels. These studies explain why clinic CCX patients report significant weight loss despite reporting normal food intake.
- Arora G., Gupta A., Narayanan S., Guo T., Iyengar P.* and Infante R.*: Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin. JCI Insight, 2018, 3(14).
- Studies Investigating Clinical Relevance of Cancer Cachexia (CCX).
As part of our comprehensive effort to understand the characteristics of cancer cachexia (CCX), we have developed databases containing the largest series of human lung, colorectal, pancreatic, and hepatic cancer patients with and without cachexia. Some of the recent results from the database evaluation highlight 1) CCX decreases survival among all thoracic and gastrointestinal cancers, 2) the disparity in the cachexia prevalence in minority populations, 3) the prevalence of this wasting syndrome even in early stage disease, and 4) early diagnosis of CCX does not alter survival due to a lack of efficacious therapies.
- Gannavarapu B., Lau S., Carter K., Cannon N., Gao A., Ahn C., Meyer J., Sher D., Jatoi A., Infante R.*, and Iyengar P.*: Prevalence and survival impact of pre-treatment cancer-associated weight loss: A tool for guiding early palliative care. Journal of Oncology Practice, 2018, 14(4):e238-e250.
- Lau S., Gannavarapu B., Carter K., Gao A., Ahn C., Meyer J., Sher, D, Jatoi A., Infante R.* and Iyengar P.*: Impact of Socioeconomic Status on Pre-Treatment Weight Loss and Survival in Non-Small Cell Lung Cancer, Journal of Oncology Practice, 2018, 14(4):e211-e220.
- Lau S., Giap F., Gannavarapu B., Westover K., Timmerman R., Choy H., Infante R.* and Iyengar P.*: Impact of Baseline Cachexia on Radiotherapy Utilization and Survival in Non-Small Cell Lung Cancer, Under Review, 2018.
- Identifying LDL-derived cholesterol intracellular transport pathway.
Most of our understanding of transport of intracellular cholesterol is derived from inhibitors of the pathway. To date, all inhibitors of cholesterol transport block stops in lysosomes limiting our understanding of post-lysosomal cholesterol trafficking. We created a post-lysosomal inhibitor of cholesterol transport using a cholesterol-binding domain of the bacterial toxin anthrolysin (ALOD4). We show that this reversible inhibitor blocks plasma membrane (PM) to ER cholesterol transport. This inhibitor provides direct evidence that LDL-derived cholesterol travels from lysosomes first to PM to meet cholesterol needs, and subsequently from PM to regulatory domains of ER to halt cholesterol uptake and synthesis. We also established that the ER continuously samples a small fraction of the PM to regulate cellular cholesterol levels.
- Abi-Mosleh L., Infante R., Radhakrishnan A., Goldstein J., and Brown M.: Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells. Proc. Natl. Acad. Sci. USA 106(46): 19316-19321, 2009.
- Infante R.* and Radhakrishnan A.*: Continuous Transport of a Small Fraction of Plasma Membrane Cholesterol to ER Regulates Total Cellular Cholesterol. eLIFE 6, 2017.
- Endapally S., Infante R.*, and Radhakrishnan A.*: Monitoring and modulating intracellular cholesterol trafficking using ALOD4, a cholesterol-binding protein. Methods in Molecular Biology, Under Review, 2018.
- Identification of Niemann-Pick Type C1 (NPC1) as a cholesterol-binding membrane protein.
NPC1 is a 1278-amino acid polytopic membrane protein that plays an essential role in the movement of LDL-derived cholesterol from lysosomes to the plasma membrane and ER. I purified NPC1> 14,000-fold from rabbit liver and discovered that its cholesterol-binding site is localized to the protein’s N-terminal 240 amino acids (NTD).
- Infante R., Abi-Mosleh L., Radhakrishnan A., Dale J., Brown M., and Goldstein, J.: Purified NPC1 Protein I. Binding of Cholesterol and Oxysterols to a 1278-Amino Acid Membrane Protein. J. Biol. Chem. 283: 1052-1063, 2008.
- Infante R., Radhakrishnan A., Abi-Mosleh L., Kinch L., Wang M., Grishin N., Goldstein J., and Brown M.: Purified NPC1 Protein II. Localization of Sterol Binding to a 240-Amino Acid Soluble Luminal Loop. J. Biol. Chem. 283: 1064-1075, 2008.
- Discovery of the “hydrophobic handoff” mechanism for cholesterol transport within lysosomes.
X-ray crystallography of NPC1’s NTD, together with biochemical and molecular biology studies, allowed us to advance the concept of the “hydrophobic handoff”. After lysosomal hydrolysis of LDL-cholesteryl esters, the NPC2 binds to the side-chain side of the cholesterol moiety. NPC2 then transfers the cholesterol to NPC1’s NTD, which binds cholesterol molecule from the opposite end (i.e., the A ring side). This “hydrophobic handoff” of cholesterol from NPC2 to NPC1 allows a single sterol to move from one protein to another during cholesterol transport, shielding it from the aqueous environment of lysosomes and preventing its precipitation.
- Infante R., Wang M., Radhakrishnan A., Kwon H., Brown M., and Goldstein J.: NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc. Natl. Acad. Sci. USA 105: 15287-15292, 2008.
- Kwon H., Abi-Mosleh L., Wang M.L., Deisenhofer J., Goldstein J., Brown M., and Infante R.E.: Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol. Cell 137(7): 1213-1224, 2009.
- Wang M., Motamed M., Infante R., Abi-Mosleh L., Kwon H., Brown, M., and Goldstein J.: Identification of Surface Residues on Niemann-Pick C2 Essential for Hydrophobic Handoff of Cholesterol to NPC1 in Lysosomes. Cell Metabolism 12(2): 166-173, 2010.