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Intestinal mitochondrial dysfunction and the gut-brain-immune axis in models of Parkinson's Disease

Award Number: K08DK134872
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Intestinal mitochondrial dysfunction and the gut-brain-immune axis in models of Parkinson's Disease - PROJECT SUMMARY Parkinson’s Disease (PD) may begin in the gastrointestinal (GI) tract. The overall goal of this research is to identify intestinal pathogenic mechanisms in PD that may lead to the identification of gut-biomarkers for early diagnosis as well as gut-directed therapies to halt progression of disease in the premotor phase. The proposed research addresses the hypothesis that mitochondrial dysfunction in the intestinal epithelium causes PD via the gut brain immune axis through two specific aims. The first aim will determine the role of mitochondrial dysfunction in mediating the response of the intestinal epithelium to enteric neuron pathologic α-Synuclein. This will be accomplished through measurement of inflammation and mitochondrial stress in duodenal tissue, isolated crypts and intestinal organoids from a PD model (mice over-expressing human α-Synuclein). In addition, these measures will be evaluated in wild type organoids treated with conditioned media from organotypic cultures of the enteric nervous system in the same PD model. The second aim will test the hypothesis that impaired mitophagy in the intestinal epithelium causes persistent central pathology and motor deficits in a gut-seeding PD model. This will be accomplished through duodenal injection of α-Synuclein preformed fibrils in mice with intestinal epithelial-specific Parkin knockout and wild type mice. This proposed research will provide Dr. Elizabeth Videlock, a board-certified Gastroenterologist, with training in the research skills necessary to study the gut-brain axis in PD. This technical training is a component of a comprehensive career development plan designed to facilitate her transition to independence. Her mentorship team is led by Nigel Maidment, Professor of Psychiatry and Biobehavioral Sciences, who has extensive experience studying dopamine neurotransmission in rodent models of PD and a strong track record in mentoring trainees to independence. Co-mentors will provide mentorship in assessment of the enteric nervous system (Million Mulugeta), intestinal organoids (Martin G. Martin), and leadership skills (Lin Chang). In addition, an advisory panel will provide mentorship for content related to the role of the gut in PD (Yvette Taché, Michael Camilleri) and mitochondrial morphology and metabolism in epithelial cells (Leanne Jones, Rajat Singh). The strength of the clinical and basic science programs in metabolism, neurodegenerative disease and the gut-brain axis make UCLA the perfect institution to support this interdisciplinary proposal.


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 = $170,532 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/21/2025	NON-COMPETING CONTINUATION	$170,532
														Subtotal = $170,532

Issue Date FY: 2024 ( Subtotal = $172,032 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/8/2024	NEW	$172,032
														Subtotal = $172,032

Grand Total All Awards = $342,564

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Intestinal mitochondrial dysfunction and the gut-brain-immune axis in models of Parkinson's Disease

Award Number: K08DK134872

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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