The ICTS-KL-2 awards are intended to support a period of mentored or independent career development in preparation for a role as an independent researcher (mentored K), or to enable and expand the grantee’s potential to make significant contributions (independent K) in the biomedical, behavioral, and clinical sciences. Generally, K awards require the candidate to hold a full-time appointment at the applicant organization and devote a minimum of 75% of that appointment to the career award. Our goal is to increase the quantity and quality of exceptionally gifted clinical researchers and translational scientists throughout the training pipeline.
Project Title: Neuroprotective interventions for cancer therapy-induced cognitive decline
Mentors: Charles Limoli PhD, Marcelo Wood PhD
Project Description: The primary career goal of Dr. Acharya is to become an independent investigator who investigates molecular and cellular mechanism(s) of radiation and chemotherapy-induced cognitive dysfunction and to develop translational neuroprotective strategies. His prior training and experience in neuroscience and regenerative medicine provide a strong foundation for a career in translational research. Under the mentorship of Drs. Limoli and Wood and expert guidance by Dr. Boison, he will learn the diverse skills required to make meaningful advances in the interdisciplinary fields of neurobiology, radiobiology and oncology. His educational background and career accomplishments demonstrate expertise in neurodegenerative disorders that adversely impact CNS functionality and cognitive health. His desire is to advance my current expertise in new directions distinct from my current research mentors, with a focus on the molecular mechanism(s) underlying the adverse side effects associated with cranial irradiation (IR) and systemic chemotherapy. By elucidating novel mechanisms relevant to neurodegenerative conditions, new insights into how the brain might respond to other endogenous or exogenous insults will be gained. Given the relative lack of information regarding the impact of radiation and chemotherapy on neurocognitive sequelae, the knowledge gained from these studies will fuel future pre-clinical/translational research to develop efficacious neuroprotective strategies and will generate important preliminary data for many extramural grant opportunities including the NIH, ACS and others.
Project Title: Evolution of Intratumoral Genetic Heterogeneity During Human Melanoma Progression: The Clones War Hypothesis
Mentors: Anand Ganesan MD, PhD; Bogi Anderson MD
Project Description: About 50% of melanomas have a mutation in BRAF, and 85-90% of BRAF mutated melanoma contain the BRAFV600E mutation. About 15% of melanomas have a mutation in NRAS, and 40‐67% of NRAS mutated melanoma contains the NRASQ61R mutation. Hence, these mutations are thought to be central drivers of tumor formation, invasion and metastasis in a significant proportion of melanomas. Whether different tumorigenic clones driven by distinct oncogenic mutations coexist during the early stages of melanoma is unknown. We hypothesize that in subsets of melanomas, different tumorigenic clones driven by either BRAFV600E or NRASQ61R are present in the same tumor during\ the early stages of melanomagenesis. During melanoma progression one clone out competes the other, resulting in one dominant oncogenic mutation (BRAFV600E or NRASQ61R) driving tumor growth. To test this hypothesis, we will break down our investigation into three aims. Aim 1: We will determine if populations of BRAFV600E mutated cells coexist with NRASQ61R mutated cells in melanoma in situ and superficially invasive melanomas. Aim 2: We will determine if the respective proportions of BRAFV600E and NRAS Q61R mutated cells are shifting towards one predominant mutated cell population in more advanced melanomas (melanomas >0.75 mm in thickness, at which point the risk of metastasis increases significantly; and metastatic melanomas. Aim 3: We will determine what other oncogenes might be mutated in melanoma in situ and early invasive melanomas in a panel of 24 other oncogenes selected for their clinical relevance in melanoma, using Targeted Next Generation Sequencing.
Project Title: Creating the next generation auditory prosthesis: improving the cochlear implant
Mentors: John Middlebrooks PhD; Fan-Gang Zeng PhD
Project Description: Creating the next generation auditory prosthesis: improving the cochlear implant. The cochlear implant is arguably the most successful present-day neural prosthesis. In best-case conditions, it brings speech recognition to profoundly deaf people. Nevertheless, even the most successful cochlear-implant users cannot understand speech in noisy environments, are unable to localize sound sources, and lack pitch perception. The lack of pitch perception, in turn, greatly limits music appreciation and recognition of the emotional content of speech and precludes understanding of tonal languages. These limitations result from the remote position of a conventional cochlear implant, separated by a bony wall from the target neural elements. Dr. Middlebrooks recently demonstrated the feasibility of an alternate mode of prosthetic auditory stimulation: a penetrating electrode array that lies in intimate contact with auditory nerve fibers. By every measure possible in short-term tests in anesthetized animals, the penetrating "intraneural" array out-performed a conventional cochlear implant, in some instances dramatically. However, the device was tested in short-term experiments that would not be suitable for long-term clinical application, and, importantly, auditory data from chronic intraneural implantation of the cochlear nerve is still lacking. I propose now to obtain this data using a commercially-available, custom-designed, chronically-implantable intraneural electrode array. I would (1) test the device first in short-term experiments intended to yield baseline values and then (2) evaluate three-month implantations in cats, monitoring long-term stability of responses and any anatomical changes. These chronic animal studies are an essential step toward translating intraneural stimulation to a practical human auditory prosthesis