1. My early work focused on the biophysics and bioenergetics of metabolic control in heart disease. This work focused on demonstrating the role of Ca2+ as a second messenger of metabolic signaling in normal and diseased hearts. This early work focused on isolated mitochondria and the control networks that coordinate oxidative phosphorylation substrate flux, and demonstrated for the first time that the F0/F1-ATPase was Ca2+ sensitive and when combined with the known effects Ca2+ on NADH production via the TCA cycle, could explain the tight coupling of energy demand by the sarcomere and ATP production by the mitochondria. This work further demonstrated that this coupling was dose dependent, very rapid, and was tightly linked to SR release of Ca2+. This body of work has helped to redefine the role of Ca2+ in energy production in normal and diseased myocardium, and has served as a platform for investigation of novel cardiac drugs in heart disease. In the body of work below, I have served as the primary or senior author in all of these studies.
a. Balaban, RS, S. Bose, S. A. French, and P.R. Territo (2003) “Role of calcium in metabolic signaling between cardiac sarcoplasmic reticulum and mitochondria in vitro.” Am J Physiol Cell Physiol. 284(2):C285-93.
b. P.R. Territo, S. A. French, and R.S. Balaban. (2001) “Simulation of cardiac work transitions, in vitro: effects of simultaneous Ca2+ and ATPase additions on isolated porcine heart mitochondria. Cell Calcium. 30(1):19-27.
c. P.R. Territo, S.A. French, M.C. Dunleavy, F.J. Evans, and R.S. Balaban (2001) “Calcium activation of oxidative phosphorylation: Rapid kinetics of mVO2, NADH and Light Scattering” J. Biol. Chem. 276: 2586-2599
d. P.R. Territo, V.K. Mootha, S.A. French, and R.S. Balaban (2000) “Activation of heart mitochondrial oxidative phosphorylation: Role of the Fo/F1ATPase.” Am. J. Physiol. 278: C423-C435.
2. A key area of focus in my career has been the development of technologies that permit determination of physiological or pharmacological function. The bulk of this work has focused on magnetic resonance imaging (MRI), x-ray computed tomography (CT), and positron emission tomography (PET) ligand development, and have enabled our teams to non-invasively probe neurological and cardiovascular function with time. In the body of work below, I have served as the primary, co-investigator, or senior author in all of these studies.
a. T. Tirkes, CY Jeon, L Li, AY Joon, TA Seltman, M Sankar, SA Persohn, and P.R. Territo. Association of Pancreatic Steatosis With Chronic Pancreatitis, Obesity, and Type 2 Diabetes Mellitus. Pancreas. 2019 Mar;48(3):420-426.
b. P.R. Territo, Riley AA, McCarthy BP, and Hutchins GD. Measurement of cardiovascular function using a novel view-sharing PET reconstruction method and tracer kinetic analysis. EJNMMI Phys. 2016 Dec;3(1):24.
c. P.R. Territo, Meyer JA, Peters JS, Riley AA, McCarthy BP, Gao M, Wang M, Green MA, Zheng QH, and Hutchins GD. Characterization of 11C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation. J Nucl Med. 2017 Mar;58(3):458-465.
d. K.K. Yoder, G.D. Hutchins, B.H. Mock, X. Fei, W.L. Winkle, B.D. Gitter, P.R. Territo, and Q.H. Zheng (2009) “Dopamine transporter binding in rat striatum: A comparison of O-methyl and N-methyl [11C]?-CFT”, Nuc. Med. Biol. Jan;36(1):11-6.
3. The development of imaging based biomarkers for in vivo testing novel therapeutics in appropriate and validated model systems are key aspects of translating model based mechanistic work to clinical applications. Our lab has focused on development of validated imaging methods in animal models and humans, and formulating a framework for quantification of the biomarkers utilizing MRI, CT, and PET as a marker of tumor growth, tumor detection, neurovascular function, and neuroinflammation. Importantly, the preclinical methods described directly translated to the clinic, thus the knowledge gained through this work provides a rapid and inexpensive method to evaluate novel therapeutic regimes non-invasively, and are often followed by bridging work to the same clinically relevant modalities. This approach in our institution has become the preferred route for novel therapeutics testing in oncology and neuroscience studies. In the body of work below, I serve as the lead, senior or co-investigator in all of these studies.
a. P.R. Territo, Zarrinmayeh H. P2X7 Receptors in Neurodegeneration: Potential Therapeutic Applications From Basic to Clinical Approaches. Front Cell Neurosci. 2021 Apr 6;15:617036.
b. Ho CY, Kindler JM, Persohn S, Kralik SF, Robertson KA, P.R. Territo. “Image segmentation of plexiform neurofibromas from a deep neural network using multiple b-value diffusion data.” Sci Rep. 2020 Oct 20;10(1):17857.
c. Gu H, P.R. Territo, Persohn SA, Bedwell AA, Eldridge K, Speedy R, Chen Z, Zheng W, Du Y. “Evaluation of chronic lead effects in the blood brain barrier system by DCE-CT”. J Trace Elem Med Biol. 2020 Dec;62:126648.
d. P.R. Territo, Maluccio M, Riley AA, McCarthy BP, Fletcher J, Tann M, Saxena R, Skill NJ. “Evaluation of 11C-acetate and 18F-FDG PET/CT in mouse multidrug resistance gene-2 deficient mouse model of hepatocellular carcinoma.” BMC Med Imaging. 2015 May 16;15:15.
4. In addition to the above listed contributions, and in collaboration with a number of investigators at IU, I have developed several model systems for the testing of novel therapeutics and/or systems. This work has focused on the formation of well characterized canine models of disease (i.e. Alzheimer’s disease, seizure), and then developed rigorous system from which to evaluate the therapeutic of interest. In virtually all cases, this paradigm has been the basis for drug candidate selection. In each of these papers, I have served as the primary investigator or co-investigator.
a. Onos KD, Quinney SK, Jones DR, Masters AR, Pandey R, Keezer KJ, Biesdorf C, Metzger IF, Meyers JA, Peters J, Persohn SC, McCarthy BP, Bedwell AA, Figueiredo LL, Cope ZA, Sasner M, Howell GR, Williams HM, Oblak AL, Lamb BT, Carter GW, Rizzo SJS, P.R. Territo. “Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study”. Alzheimers Dement (N Y). 2022 Aug 23;8(1):e12329.
b. Oblak AL, Cope ZA, Quinney SK, Pandey RS, Biesdorf C, Masters AR, Onos KD, Haynes L, Keezer KJ, Meyer JA, Peters JS, Persohn SA, Bedwell AA, Eldridge K, Speedy R, Little G, Williams SP, Noarbe B, Obenaus A, Sasner M, Howell GR, Carter GW, Williams H, Lamb BT, P.R. Territo, Sukoff Rizzo SJ. Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice. Alzheimers Dement (N Y). 2022 Jul 14;8(1):e12317.
c. P.R. Territo, H.E. Shannon, K. Newhall, S.D. Barnhart, S.C. Peters, D.R. Engleking, T. Bin, T.J. Burnett, J.M. Rodewald, B. Abdul-Karim, K.J. Freise. “Nonlinear Mixed Effects Pharmacokinetic/Pharmacodynamic Analysis of the Anticonvulsant Ameltolide (LY201116) In A Canine Seizure Model.” J Vet Pharmacol Ther. (2008) Dec;31(6):562-70.
d. P.R. Territo, K.J. Freise, K. Newhall, S.D. Barnhart, S.C. Peters, D.R. Engleking, T.J. Burnett, B. Abdul-Karim, H.E. Shannon. (2007) “Development and Validation of the Maximal Electro-Shock Seizure Model in Dogs” J Vet Pharmacol Ther. Dec;30(6):508-15.
Complete List of Published Work in My Bibliography:http://www.ncbi.nlm.nih.gov/sites/myncbi/paul.territo.1/bibliography/48023526/public/?sort=date&direction=ascending