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Mechanisms underlying spontaneous firing by motoneurons with acute neurotoxicity

Award Number: R01CA268125
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms underlying spontaneous firing by motoneurons with acute neurotoxicity - Abstract The toxic effects of platinum-based compounds (PBCs) commonly used in chemotherapy weigh against their usefulness as the major option for successfully combating lethal cancers. The decision to opt for survival leaves people worldwide to suffer with PBC neurotoxicity that reduces quality of life by causing neurological disorders both during and long after treatment. Pain, strange sensations, fatigue, and difficulty with balance and walking are common symptoms, collectively known as chemotherapy-induced neuropathy (CIN). During treatment, both sensory and motor neurons are observed to fire unintentionally, i.e. they exhibit spontaneous firing (SA), and evidence suggests that SA bears responsibility for the earliest signs of distress, including uncontrolled muscle contraction, cramping, and unusual body sensations. Prolonged impact of SA is suggested by observations that the intensity of acute signs and symptoms of toxicity is predictive of the severity of symptoms that develop after with PBC accumulation and persist for months or years after treatment. This situation describes the urgent need for prevention or treatment of PBC effects on abnormal neuronal activity and its underlying causes, but no effective solution has been found. The research project proposed here is designed to meet this need by examining the effects of human-scaled doses of PBC on motor neurons in cancer-bearing rats studied in vivo. The proposal prioritizes three specific aims as the most logical and impactful next steps, all supported and proven feasible by preliminary experiments and findings. Aim 1 will test whether PBC accumulation in motor neuron cell bodies within the central nervous system (CNS) is necessary or sufficient to induce SA. Emphasis on the CNS is a new direction in the field that breaks with common, yet untested consensus that SA originates at unusual, i.e. ectopic sites of firing out in the peripheral nervous system. This new direction is driven by recent and conclusive findings presented here that SA in motor neurons is produced within the CNS. A possible cause of SA will be tested using methods to measure and manipulate PBC accumulation in motoneurons. Aim 2 will take advantage of the exceptional access of spinal motor neurons for studying, within a living animal, the biophysical mechanisms underlying changes in neuronal excitability and SA. The results will provide the first ever detail about the effects of PBC on intrinsic excitability of motor neurons and will guide understanding of effects that are entirely unknown for other neurons in the CNS. Aim 3 will test the possibility that SA in motor neurons is driven synaptically by SA shown here for sensory neurons. This systematic examination of SA induced by PBC neurotoxicity will significantly advance the field by critically assessing three major candidate mechanisms having strong potential for evidence-based impact on urgently needed development of preventative measures or treatments.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $431,596 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	000	4	1/7/2025	NON-COMPETING CONTINUATION	$431,596
														Subtotal = $431,596

Issue Date FY: 2024 ( Subtotal = $462,934 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$24,365
2024	2024	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	000	3	1/15/2024	NON-COMPETING CONTINUATION	$438,569
														Subtotal = $462,934

Issue Date FY: 2023 ( Subtotal = $484,899 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	000	2	4/4/2023	NON-COMPETING CONTINUATION	$484,899
														Subtotal = $484,899

Issue Date FY: 2022 ( Subtotal = $507,639 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	000	1	2/11/2022	NEW	$507,639
														Subtotal = $507,639

Grand Total All Awards = $1,887,068

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Mechanisms underlying spontaneous firing by motoneurons with acute neurotoxicity

Award Number: R01CA268125

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/11/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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